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Rosuvastatin

PubChem CID
446157
Structure
Rosuvastatin_small.png
Rosuvastatin_3D_Structure.png
Molecular Formula
Synonyms
  • Rosuvastatin
  • 287714-41-4
  • Creston
  • X-Plended
  • Rosuvastatin calcium
Molecular Weight
481.5 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-06-24
  • Modify:
    2025-01-18
Description
Rosuvastatin is a dihydroxy monocarboxylic acid that is (6E)-7-{4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl} hept-6-enoic acid carrying two hydroxy substituents at positions 3 and 5 (the 3R,5S-diastereomer). It has a role as an antilipemic drug, an anti-inflammatory agent, a CETP inhibitor, a cardioprotective agent, a xenobiotic and an environmental contaminant. It is a member of pyrimidines, a sulfonamide, a dihydroxy monocarboxylic acid, a statin (synthetic) and a member of monofluorobenzenes. It is functionally related to a hept-6-enoic acid. It is a conjugate acid of a rosuvastatin(1-).
Rosuvastatin, also known as the brand name product Crestor, is a lipid-lowering drug that belongs to the statin class of medications, which are used to lower the risk of cardiovascular disease and manage elevated lipid levels by inhibiting the endogenous production of cholesterol in the liver. More specifically, statin medications competitively inhibit the enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) Reductase, which catalyzes the conversion of HMG-CoA to mevalonic acid and is the third step in a sequence of metabolic reactions involved in the production of several compounds involved in lipid metabolism and transport including cholesterol, low-density lipoprotein (LDL) (sometimes referred to as "bad cholesterol"), and very low-density lipoprotein (VLDL). Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD, such as those with Type 2 Diabetes. The clear evidence of the benefit of statin use coupled with very minimal side effects or long term effects has resulted in this class becoming one of the most widely prescribed medications in North America. Rosuvastatin and other drugs from the statin class of medications including [atorvastatin], [pravastatin], [simvastatin], [fluvastatin], and [lovastatin] are considered first-line options for the treatment of dyslipidemia. This is largely due to the fact that cardiovascular disease (CVD), which includes heart attack, atherosclerosis, angina, peripheral artery disease, and stroke, has become a leading cause of death in high-income countries and a major cause of morbidity around the world. 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 <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. While all statin medications are considered equally effective from a clinical standpoint, rosuvastatin is considered the most potent; doses of 10 to 40mg rosuvastatin per day were found in clinical studies to result in a 45.8% to 54.6% decreases in LDL cholesterol levels, which is about three-fold more potent than [atorvastatin]'s effects on LDL cholesterol. However, the results of the SATURN trial concluded that despite this difference in potency, there was no difference in their effect on the progression of coronary atherosclerosis. Rosuvastatin is also a unique member of the class of statins due to its high hydrophilicity which increases hepatic uptake at the site of action, low bioavailability, and minimal metabolism via the Cytochrome P450 system. This last point results in less risk of drug-drug interactions compared to [atorvastatin], [lovastatin], and [simvastatin], which are all extensively metabolized by Cytochrome P450 (CYP) 3A4, an enzyme involved in the metabolism of many commonly used drugs. Drugs such as [ciclosporin], [gemfibrozil], and some antiretrovirals are more likely to interact with this statin through antagonism of OATP1B1 organic anion transporter protein 1B1-mediated hepatic uptake of rosuvastatin.
Rosuvastatin is a HMG-CoA Reductase Inhibitor. The mechanism of action of rosuvastatin is as a Hydroxymethylglutaryl-CoA Reductase Inhibitor.
See also: Rosuvastatin Calcium (has salt form); Rosuvastatin Zinc (has salt form).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Rosuvastatin.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(E,3R,5S)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C22H28FN3O6S/c1-13(2)20-18(10-9-16(27)11-17(28)12-19(29)30)21(14-5-7-15(23)8-6-14)25-22(24-20)26(3)33(4,31)32/h5-10,13,16-17,27-28H,11-12H2,1-4H3,(H,29,30)/b10-9+/t16-,17-/m1/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

BPRHUIZQVSMCRT-VEUZHWNKSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC(C)C1=NC(=NC(=C1/C=C/[C@H](C[C@H](CC(=O)O)O)O)C2=CC=C(C=C2)F)N(C)S(=O)(=O)C
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C22H28FN3O6S
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

147098-20-2

2.3.3 Deprecated CAS

1354641-86-3

2.3.4 European Community (EC) Number

2.3.5 UNII

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Metabolomics Workbench ID

2.3.13 NCI Thesaurus Code

2.3.14 Nikkaji Number

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Calcium, Rosuvastatin
  • Crestor
  • rosuvastatin
  • rosuvastatin calcium
  • ZD 4522
  • ZD4522

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
481.5 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
1.6
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
10
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
10
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
481.16828496 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
481.16828496 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
149 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
33
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
767
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Solubility

Sparingly soluble in water
FDA label
8.86e-02 g/L

3.2.3 LogP

0.13
FDA label
Kow = 0.13 (pH 7.0) /log Kow = -0.88/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1540
2.4

3.2.4 Stability / Shelf Life

Stable under recommended storage conditions. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html

3.2.5 Optical Rotation

White powder from water as the monohydrate; begins to melt at 155 °C with no definitive MP. Specific optical rotation: +14.8 deg at 24 °C/D (c = 1.012 in 50% methanol). Sparingly soluble in water, methanol; slightly soluble in ethanol /Rosuvastatin calcium salt/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1540

3.2.6 Ionization Efficiency

Ionization mode
Positive
logIE
2.53
pH
2.7
Instrument
Agilent XCT
Ion source
Electrospray ionization
Additive
formic acid (5.3nM)
Organic modifier
MeCN (80%)
Reference
DOI:

3.2.7 Collision Cross Section

217.65 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

210.73 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

213.85 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.8 Other Experimental Properties

pKa = 4.76; log Kow = 0.26-0.30 at pH 7.0. Solubility in water: 3820 mg/L (pH 5), 22,000 mg/L (pH 7), 4860 mg/l (pH 9). /Rosuvastatin calcium/
AstraZeneca. Environmental Risk Assessment Data. Rosuvastatin calcium. Available from, as of Dec 13, 2016: https://www.astrazeneca.com/content/dam/az/our-company/Sustainability/Rosuvastatin-Calcium.pdf

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Statins
S44 | STATINS | Statins Collection from Public Resources | DOI:10.5281/zenodo.2656736
Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals -> Antilipidemics
S57 | GREEKPHARMA | Suspect Pharmaceuticals from the National Organization of Medicine, Greece | DOI:10.5281/zenodo.3248883
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Anticholesteremic Agents; Antilipemic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors
Human drug -> Prescription; Discontinued; Active ingredient (ROSUVASTATIN CALCIUM)
Paediatric drug

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 LC-MS

1 of 31
View All
Authors
Stravs M, Schymanski E, Singer H, Department of Environmental Chemistry, Eawag
Instrument
LTQ Orbitrap XL Thermo Scientific
Instrument Type
LC-ESI-ITFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
35 % (nominal)
Fragmentation Mode
CID
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
9.2 min
Precursor m/z
482.1756
Precursor Adduct
[M+H]+
Top 5 Peaks

446.1541 999

464.1648 647

376.1489 387

402.1638 246

422.1543 200

Thumbnail
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License
CC BY
2 of 31
View All
Authors
Stravs M, Schymanski E, Singer H, Department of Environmental Chemistry, Eawag
Instrument
LTQ Orbitrap XL Thermo Scientific
Instrument Type
LC-ESI-ITFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
15 % (nominal)
Fragmentation Mode
HCD
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
9.2 min
Precursor m/z
482.1756
Precursor Adduct
[M+H]+
Top 5 Peaks
482.1751 999
Thumbnail
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License
CC BY

4.1.2 Other MS

1 of 2
Authors
K.A. Wilkinson & S.N. Miranda
Instrument
Xevo G2 XS QTOF, waters
Instrument Type
ESI-QTOF
MS Level
MS2
Ionization Mode
NEGATIVE
Ionization
ESI
Collision Energy
18eV
Precursor m/z
480.161
Precursor Adduct
[M-H]-
Top 5 Peaks

418.1599 999

340.1823 545

298.1353 231

338.1665 159

480.16 145

Thumbnail
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License
CC BY
2 of 2
MoNA ID
MS Category
Experimental
MS Type
Other
MS Level
MS2
Precursor Type
[M-H]-
Precursor m/z
480.161
Instrument
Xevo G2 XS QTOF, waters
Instrument Type
ESI-QTOF
Ionization
ESI
Ionization Mode
negative
Collision Energy
18eV
Top 5 Peaks

418.1599 100

340.1823 54.58

298.1353 23.09

338.1665 15.87

480.1600 14.47

Thumbnail
Thumbnail
License
CC BY

4.2 IR Spectra

4.2.1 FTIR Spectra

Instrument Name
Bio-Rad FTS
Technique
KBr0
Source of Spectrum
Forensic Spectral Research
Source of Sample
Cayman Chemical Company
Catalog Number
<a href=https://www.caymanchem.com/product/12029>12029</a>
Lot Number
0444392-62
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.2.2 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Neat
Source of Spectrum
Forensic Spectral Research
Source of Sample
Cayman Chemical Company
Catalog Number
<a href=https://www.caymanchem.com/product/12029>12029</a>
Lot Number
0444392-62
Copyright
Copyright © 2019-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.3 Raman Spectra

Technique
FT-Raman
Source of Spectrum
Forensic Spectral Research
Source of Sample
Cayman Chemical Company
Catalog Number
<a href=https://www.caymanchem.com/product/12029>12029</a>
Lot Number
0444392-62
Copyright
Copyright © 2015-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

The FDA monograph states that rosuvastatin is indicated as an adjunct to diet in the treatment of triglyceridemia, Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia), and Homozygous Familial Hypercholesterolemia. The Health Canada monograph for rosuvastatin further specifies that rosuvastatin is indicated for the reduction of elevated total cholesterol (Total-C), LDL-C, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C in hyperlipidemic and dyslipidemic conditions when response to diet and exercise alone has been inadequate. It is also indicated for the prevention of major cardiovascular events (including risk of myocardial infarction, nonfatal stroke, and coronary artery revascularization) in adult patients without documented history of cardiovascular or cerebrovascular events, but with at least two conventional risk factors for cardiovascular disease. Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels.
Homozygous Familial Hypercholesterolaemia, Prevention of cardiovascular events, Primary combined (mixed) dyslipidaemia, Primary hypercholesterolaemia

7.2 LiverTox Summary

Rosuvastatin is a commonly used cholesterol lowering agent (statin) that is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy, and rarely with clinically apparent acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Anticholesteremic Agents; Antilipemic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors
Antilipemic Agents

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 Drug Labels

Drug and label
Active ingredient and drug
Drug and label
Active ingredient and drug

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.8.3 NIPH Clinical Trials Search of Japan

7.9 EMA Drug Information

Type
Paediatric investigation
Active Substance
Therapeutic Area
Cardiovascular diseases
Drug Form
Film-coated tablet
Administration Route
Oral use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2010-11-24

7.10 Therapeutic Uses

Hydroxymethylglutaryl-CoA Reductase Inhibitors
National Library of Medicine's Medical Subject Headings. Rosuvastatin. Online file (MeSH, 2016). Available from, as of November 28, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Rosuvastatin is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of February 1, 2017: https://clinicaltrials.gov/ct2/results?term=ROSUVASTATIN&Search=Search
In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age >/= 50 years old in men and >/= 60 years old in women, hsCRP >/= 2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease, Crestor is indicated to: reduce the risk of stroke, reduce the risk of myocardial infarction, reduce the risk of arterial revascularization procedures. /Included in US product label/
Crestor is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels. /Included in US product label/
For more Therapeutic Uses (Complete) data for Rosuvastatin (11 total), please visit the HSDB record page.

7.11 Drug Warnings

Crestor 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 Crestor during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Crestor may cause fetal harm when administered to pregnant women. Crestor should be discontinued as soon as pregnancy is recognized.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
Crestor should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age >/= 65 years, inadequately treated hypothyroidism, renal impairment).
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported in patients receiving statins, including rosuvastatin. These adverse effects can occur at any dosage, but the risk is increased with the highest dosage of rosuvastatin (40 mg daily).
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1865
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins. Immune-mediated necrotizing myopathy is characterized by proximal muscle weakness and elevated creatine kinase (CK, creatine phosphokinase, CPK) concentrations that persist despite discontinuance of statin therapy, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1865
For more Drug Warnings (Complete) data for Rosuvastatin (22 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

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 <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. **Skeletal Muscle Effects** Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg). Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of some other lipid-lowering therapies (such as [fenofibrate] or [niacin]), [gemfibrozil], [cyclosporine], [atazanavir]/[ritonavir], [lopinavir]/ritonavir, or [simeprevir]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together. Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment. **Liver Enzyme Abnormalities** Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. **Endocrine Effects** Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium tablets. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus. An in vitro study found that [atorvastatin], [pravastatin], [rosuvastatin], and [pitavastatin] exhibited a dose-dependent cytotoxic effect on human pancreas islet β cells, with reductions in cell viability of 32, 41, 34 and 29%, respectively, versus control]. Moreover, insulin secretion rates were decreased by 34, 30, 27 and 19%, respectively, relative to control. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Rosuvastatin demonstrated no effect upon nonstimulated cortisol levels and no effect on thyroid metabolism as assessed by TSH plasma concentration. In rosuvastatin treated patients, there was no impairment of adrenocortical reserve and no reduction in plasma cortisol concentrations. Clinical studies with other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma testosterone concentration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied. The effects, if any, on the pituitarygonadal axis in premenopausal women are unknown. **Cardiovascular** Ubiquinone levels were not measured in rosuvastatin clinical trials, however significant decreases in circulating ubiquinone levels in patients treated with other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure. **Lipoprotein A** In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [Lp(a)] concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high-risk patients placed on rosuvastatin therapy. Further studies have demonstrated statins affect Lp(a) levels differently in patients with dyslipidemia depending on their apo(a) phenotype; statins increase Lp(a) levels exclusively in patients with the low molecular weight apo(a) phenotype.

8.2 MeSH Pharmacological Classification

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis. (See all compounds classified as Hydroxymethylglutaryl-CoA Reductase Inhibitors.)
Anticholesteremic Agents
Substances used to lower plasma cholesterol levels. (See all compounds classified as Anticholesteremic Agents.)

8.3 FDA Pharmacological Classification

1 of 3
FDA UNII
413KH5ZJ73
Active Moiety
ROSUVASTATIN
Pharmacological Classes
Established Pharmacologic Class [EPC] - HMG-CoA Reductase Inhibitor
Pharmacological Classes
Mechanisms of Action [MoA] - Hydroxymethylglutaryl-CoA Reductase Inhibitors
FDA Pharmacology Summary
Rosuvastatin is a HMG-CoA Reductase Inhibitor. The mechanism of action of rosuvastatin is as a Hydroxymethylglutaryl-CoA Reductase Inhibitor.
2 of 3
Non-Proprietary Name
ROSUVASTATIN
Pharmacological Classes
HMG-CoA Reductase Inhibitor [EPC]; Hydroxymethylglutaryl-CoA Reductase Inhibitors [MoA]
3 of 3
Non-Proprietary Name
ROSUVASTATIN CALCIUM
Pharmacological Classes
HMG-CoA Reductase Inhibitor [EPC]; Hydroxymethylglutaryl-CoA Reductase Inhibitors [MoA]

8.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

C - Cardiovascular system

C10 - Lipid modifying agents

C10A - Lipid modifying agents, plain

C10AA - Hmg coa reductase inhibitors

C10AA07 - Rosuvastatin

8.5 Absorption, Distribution and Excretion

Absorption
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.
Route of Elimination
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.
Volume of Distribution
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.
In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to Crestor dose. The absolute bioavailability of rosuvastatin is approximately 20%. Administration of Crestor with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
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.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
/MILK/ Limited data indicate that Crestor is present in human milk.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
For more Absorption, Distribution and Excretion (Complete) data for Rosuvastatin (7 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

Rosuvastatin is not extensively metabolized, as demonstrated by the small amount of radiolabeled dose that is recovered as a metabolite (~10%). Cytochrome P450 (CYP) 2C9 is primarily responsible for the formation of rosuvastatin's major metabolite, N-desmethylrosuvastatin, which has approximately 20-50% of the pharmacological activity of its parent compound in vitro. However, this metabolic pathway isn't deemed to be clinically significant as there were no observable effects found on rosuvastatin pharmacokinetics when rosuvastatin was coadministered with fluconazole, a potent CYP2C9 inhibitor. In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as substrate, inhibitor or inducer). Consequently, there is little potential for drug-drug interactions upon coadministration with agents that are metabolized by cytochrome P450.
Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
Not extensively metabolized. Only ~10% is excreted as metabolite. Cytochrome P450 (CYP) 2C9 is primarily responsible for the formation of rosuvastatin's major metabolite, N-desmethylrosuvastatin. N-desmethylrosuvastatin has approximately 50% of the pharmacological activity of its parent compound in vitro. Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin accounts for greater than 90% of the pharmacologic action. Inhibitors of CYP2C9 increase the AUC by less than 2-fold. This interaction does not appear to be clinically significant. Route of Elimination: 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. Half Life: 19 hours

8.7 Biological Half-Life

The elimination half-life (t½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses.
The elimination half-life of rosuvastatin is approximately 19 hours.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512

8.8 Mechanism of Action

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.
Crestor 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.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Extracellular
  • Membrane

8.9.2 Metabolite Pathways

8.10 Transformations

9 Use and Manufacturing

9.1 Uses

Hydroxymethylglutaryl-CoA Reductase Inhibitors
National Library of Medicine's Medical Subject Headings. Rosuvastatin. Online file (MeSH, 2016). Available from, as of November 28, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
MEDICATION

Use (kg; approx.) in Germany (2009): >100

Consumption (g per capita; approx.) in Germany (2009): 0.00122

Calculated removal (%): 24.7

Used as an adjunct to dietary therapy to treat primary hyperlipidemia (heterozygous familial and nonfamilial), mixed dyslipidemia and hypertriglyceridemia. Also indicated for homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies or when other such therapies are not available. Furthermore, it is used to slow the progression of atherosclerosis and for primary prevention of cardiovascular disease.

9.1.1 Use Classification

Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

The preparation of the intermediate ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-carboxylate occur according to standard chemical procedures. Reduction to the 5-hydroxymethyl derivative proceeds smoothly with diisobutylaluminum hydride (DIBALH) in toluene at -10 °C. The hydroxymethyl group is then converted to the bromo derivative, which upon reaction with triphenylphosphine affords the Wittig reagent. The latter is treated with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate and provides the protected rosuvastatin ester. Removal of the dioxane protecting group by HCl, ester hydrolysis with NaOH and precipitation with CaCl2 gives /rosuvastatin/. The 6-formyl side chain intermediate is prepared by oxidation of the corresponding 6-hydroxymethyl compound, e.g., with DMSO-oxalyl chloride.
Kleemann A; Cardiovascular Drugs. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2017). NY, NY: John Wiley & Sons. Online Posting Date: January 15, 2008
Preparation: K. Hirai et al., European Patent Office patent 521471; eidem, United States of America patent 5260440 (both 1993 to Shionogi).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1540

9.3 Formulations / Preparations

Table: Rosuvastatin Preparations
Route of Administration
Oral
Dosage Form
Tablets
Strength
5 mg (of rosuvastatin)
Brand or Generic Form (Manufacturer)
Crestor (AstraZeneca)
Route of Administration
Oral
Dosage Form
Tablets
Strength
10 mg (of rosuvastatin)
Brand or Generic Form (Manufacturer)
Crestor (AstraZeneca)
Route of Administration
Oral
Dosage Form
Tablets
Strength
20 mg (of rosuvastatin)
Brand or Generic Form (Manufacturer)
Crestor (AstraZeneca)
Route of Administration
Oral
Dosage Form
Tablets
Strength
40 mg (of rosuvastatin)
Brand or Generic Form (Manufacturer)
Crestor (AstraZeneca)
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1867

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

1 of 2
View All
Pictogram(s)
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H350 (82.3%): May cause cancer [Danger Carcinogenicity]

H360 (89.9%): May damage fertility or the unborn child [Danger Reproductive toxicity]

H370 (82.3%): Causes damage to organs [Danger Specific target organ toxicity, single exposure]

H372 (88%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

H410 (87.3%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P260, P264, P270, P273, P280, P308+P316, P318, P319, P321, P391, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 158 reports by companies from 18 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

10.1.2 Hazard Classes and Categories

Carc. 1B (82.3%)

Repr. 1B (89.9%)

STOT SE 1 (82.3%)

STOT RE 1 (88%)

Aquatic Chronic 1 (87.3%)

Carc. 2 (100%)

Repr. 1B (100%)

Aquatic Chronic 3 (100%)

10.2 Fire Fighting

10.2.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html

10.3 Accidental Release Measures

10.3.1 Cleanup Methods

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html

10.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html

10.3.3 Preventive Measures

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
Precautions for safe handling: Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: General industrial hygiene practice. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

10.4 Handling and Storage

10.4.1 Storage Conditions

Store at controlled room temperature, 20-25 °C (68-77 °F). Protect from moisture.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
Keep container tightly closed in a dry and well-ventilated place. Storage class (TRGS 510): Non Combustible Solids. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html

10.5 Exposure Control and Personal Protection

10.5.1 Personal Protective Equipment (PPE)

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html
Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html

10.6 Stability and Reactivity

10.6.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents. /Rosuvastatin calcium/
Sigma-Aldrich; Safety Data Sheet for Rosuvastatin calcium. Product Number: SML1264, Version 5.0 (Revision Date 04/23/2015). Available from, as of January 19, 2017: https://www.sigmaaldrich.com/safety-center.html

10.7 Regulatory Information

10.7.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including rosuvastatin calcium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Rosuvastatin calcium/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 1, 2017: https://www.fda.gov/cder/ob/

11 Toxicity

11.1 Toxicological Information

11.1.1 Toxicity Summary

IDENTIFICATION AND USE: Rosuvastatin is hydroxymethylglutaryl-CoA reductase inhibitor. It is is indicated to reduce the risk of stroke, myocardial infarction, and arterial revascularization procedures. HUMAN EXPOSURE AND TOXICITY: Rosuvastatin is the most potent 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor commercially available to lower low-density lipoprotein cholesterol. Rosuvastatin has been associated with several adverse effects, including rhabdomyolysis and arthralgias. Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported in patients receiving statins, including rosuvastatin. These adverse effects can occur at any dosage, but the risk is increased with the highest dosage of rosuvastatin (40 mg daily). There is a report of Takotsubo cardiomyopathy, triggered by delayed-onset rhabdomyolysis following the administration of long-term rosuvastatin treatment, without any preceding stressors or changes in the patient's medical condition, in association with complaints of non-specific muscle-related symptoms. Literature reported the case of a marathon runner who presented with acute rhabdomyolysis during competition while being under rosuvastatin treatment. A 77-year-old patient developed acute pancreatitis after treatment with rosuvastatin, which resolved on withdrawal of the medication. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. The genotoxic potential of rosuvastatin was assessed by chromosomal aberrations (CAs), micronucleus (MN) and DNA damage by comet assay in human peripheral blood lymphocytes. According to these results, rosuvastatin is cytotoxic and clastogenic/aneugenic in human peripheral lymphocytes. ANIMAL STUDIES: Rosuvastatin was shown to be of low acute toxicity following administration of single doses to rats and dogs by oral and intravenous routes. There were no mortalities in rats given an oral dose of 1000 mg/kg or 2000 mg/kg, and other than depression of bodyweight at 2000 mg/kg, there were no treatment-related effects at either dose level. Dogs received oral doses of 1000 mg/kg or 2000 mg/kg with vomiting on the day of dosing observed as the major clinical finding in both sexes. In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60 or 80 mg/kg/day, the incidence of uterine polyps was statistically significantly increased only in females at the dose of 80 mg/kg/day. In a 107-week carcinogenicity study in mice given 10, 60, 200 or 400 mg/kg/day, the 400 mg/kg/day dose was poorly tolerated, resulting in early termination of this dose group. An increased incidence of hepatocellular carcinomas was observed at 200 mg/kg/day and an increase in hepatocellular adenomas was seen at 60 and 200 mg/kg/day. Rosuvastatin administration did not indicate a teratogenic effect in rats at
Rosuvastatin is a competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the liver. 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. Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adherence and transmigration (A2814). The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts (A2818). Rosuvastatin increases the bioavailability of nitric oxide (A2814, 12031849, 15914111) by upregulating NOS (A2816) and by increasing the stability of NOS through post-transcriptional polyadenylation (A7824). It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid.
A2814: Stalker TJ, Lefer AM, Scalia R: A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: the role of mevalonic acid. Br J Pharmacol. 2001 Jun;133(3):406-12. PMID:11375257
A2816: Jones SP, Gibson MF, Rimmer DM 3rd, Gibson TM, Sharp BR, Lefer DJ: Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor. J Am Coll Cardiol. 2002 Sep 18;40(6):1172-8. PMID:12354446
A2818: Di Napoli P, Taccardi AA, Grilli A, De Lutiis MA, Barsotti A, Felaco M, De Caterina R: Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts. Cardiovasc Res. 2005 Jun 1;66(3):462-71. Epub 2005 Mar 2. PMID:15914111
A7824: Kosmidou I, Moore JP, Weber M, Searles CD: Statin treatment and 3' polyadenylation of eNOS mRNA. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2642-9. Epub 2007 Oct 4. PMID:17916773

11.1.2 Hepatotoxicity

Rosuvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 3% of patients. ALT levels above 3 times the upper limit of normal (ULN) occur slightly more frequently among rosuvastatin treated [1.1%] than placebo [0.5%] recipients. Serum enzyme elevations are more common with higher doses of rosuvastatin, being 2.2% with 40 mg daily. Most of these elevations are self-limited and do not require dose modification. Rosuvastatin is also associated with frank, clinically apparent hepatic injury but this is rare, occurring in less than 1:10,000 patients. The onset is typically after 2 to 4 months ,and the pattern of serum enzyme elevations is usually hepatocellular, although cholestatic cases have also been reported. Rash, fever and eosinophilia are uncommon. Several statins including rosuvastatin have been linked to hepatitis with autoimmune features marked by ANA positivity, elevations in serum immunoglobulin levels, and a clinical response to corticosteroids. Such features are not, however, invariable (Case 1). The injury is usually self-limited and resolves rapidly once rosuvastatin is stopped, but it can be severe and fatal instances have been reported.

Likelihood score: A (likely cause of clinically apparent liver injury).

11.1.3 Drug Induced Liver Injury

Compound
rosuvastatin
DILI Annotation
Less-DILI-Concern
Severity Grade
3
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.4 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

11.1.5 Health Effects

Health effects include abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities (A308).
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

11.1.6 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Levels of rosuvastatin in milk are low, but no relevant published information exists with its use during breastfeeding. The consensus opinion is that women taking a statin should not breastfeed because of a concern with disruption of infant lipid metabolism. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with rosuvastatin and pravastatin. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

A possible case of rosuvastatin-induced gynecomastia has been reported. Serum prolactin was not measured.

11.1.7 Exposure Routes

Inhalation. Bioavailability is approximately 20%. Peak plasma concentrations were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to CRESTOR dose. Food has no effect on the AUC of rosuvastatin.

11.1.8 Symptoms

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 Caucasians patients.

11.1.9 Treatment

After ingestion exposure, administer charcoal as a slurry. In case of Rhabdomyolosis, administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. (L1160)
L1160: Wikipedia. Tramadol. Last Updated 8 August 2009. http://en.wikipedia.org/wiki/Tramadol

11.1.10 Interactions

Concomitant use of rosuvastatin and ritonavir-boosted tipranavir produces minimal to no change in exposure to rosuvastatin. Following concomitant use of rosuvastatin (10 mg as a single dose) and ritonavir-boosted tipranavir (tipranavir 500 mg with ritonavir 200 mg twice daily for 11 days), rosuvastatin peak plasma concentration and AUC were increased by twofold and 26%, respectively. Caution is advised if rosuvastatin is used concomitantly with ritonavir-boosted tipranavir.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1866
Concomitant use of rosuvastatin and antilipemic dosages (1 g daily or higher) of niacin may increase the risk of myopathy. Data from several large randomized studies indicate that concomitant use of niacin (1.5-2 g daily) with another statin (i.e., simvastatin 40-80 mg once daily, with or without ezetimibe) resulted in an increased risk of severe adverse effects, including disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, and bleeding. Caution is advised if rosuvastatin is used concomitantly with antilipemic dosages of niacin.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1867
Following concomitant use of rosuvastatin (single 20-mg dose) with lomitapide (10 mg once daily for 7 days), peak plasma concentration and AUC of rosuvastatin were increased by 6 and 2%, respectively. Following concomitant use of rosuvastatin (single 20-mg dose) with lomitapide (60 mg once daily for 7 days), peak plasma concentration and AUC of rosuvastatin were increased by 4 and 32%, respectively. Dosage adjustment of rosuvastatin is not required during concomitant use with lomitapide.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1867
Concomitant use of rosuvastatin (80 mg as a single dose) and ketoconazole (200 mg twice daily for 7 days) decreased rosuvastatin peak plasma concentration by 5% and increased rosuvastatin AUC by 2%.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1866
For more Interactions (Complete) data for Rosuvastatin (25 total), please visit the HSDB record page.

11.1.11 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1
There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512

11.1.12 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported in patients receiving statins, including rosuvastatin. These adverse effects can occur at any dosage, but the risk is increased with the highest dosage of rosuvastatin (40 mg daily).
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1865
/SIGNS AND SYMPTOMS/ There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Crestor, promptly interrupt therapy. If an alternate etiology is not found, do not restart Crestor.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
/CASE REPORTS/ A 66-year-old man with diabetes and hypertension using statin was admitted to the hospital with progressive myalgia. He had been on rosuvastatin for five months. After beginning the use of phosphodiesterase-5 inhibitors, he presented with severe muscle pain and maintained penile erection. Several days after interruption of therapy, muscle pain and penile erection disappeared. This case demonstrates the interaction of sildenafil with rosuvastatin might result in myopathy.
Pennisi G et al; South Med J 103 (10): 1052-4 (2010)
/CASE REPORTS/ A 66 year-old woman with no history of renal or liver disease presented with progressive asthenia and diffuse myalgia. She cited 5 months history of mild hyperlipidemia under treatment with rosuvastatin (10 mg/day). Clinical examination documented both an increase in liver size and proximal muscle weakness, with difficulty in raising arms above the head. Blood tests showed the presence of renal, liver and muscle failure, with no evidence of virological, immunological or hematological diseases. Rosuvastatin treatment was stopped and blood values normalized within five days; but because of an increase in cholesterol plasma levels, rosuvastatin (10 mg/day) was restarted. Two days later, the patient returned to our observation due to the development of asthenia and muscle weakness, with an increase in creatine phosphokinase, 12,165 U/L. Rosuvastatin was discontinued and replaced with pravastatin (40 mg/day) with a complete resolution of clinical and laboratory findings in about six days. Our patient was taking rosuvastatin, warfarin and telmisartan, which are metabolized by CYP2C9; we therefore hypothesized that the rosuvastatin-induced rhabdomyolysis was probably by CYP2C9 enzyme saturation.
Gallelli L et al; Drug Metabol Drug Interact. 2009;24(1):83-7 (2009)
For more Human Toxicity Excerpts (Complete) data for Rosuvastatin (22 total), please visit the HSDB record page.

11.1.13 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Rosuvastatin was shown to be of low acute toxicity following administration of single doses to rats and dogs by oral and intravenous routes. There were no mortalities in rats given an oral dose of 1000 mg/kg or 2000 mg/kg, and other than depression of bodyweight at 2000 mg/kg, there were no treatment-related effects at either dose level. Dogs received oral doses of 1000 mg/kg or 2000 mg/kg with vomiting on the day of dosing observed as the major clinical finding in both sexes. Biochemical changes (increased plasma enzymes, decreased lipids) and hematological change (increased white blood cells) were found in dogs given an oral dose of up to and including 2000 mg/kg. Lethality was observed immediately after dosing in 1/1 of rats given an intravenous dose of 500 mg/kg but two rats given 250 mg/kg intravenously showed slight hypopnea and weakness soon after dosing with no subsequent effects.
Health Canada; Product Monograph for Rosuvastatin Calcium Tablets (5 mg, 10 mg, 20 mg and 40 mg of Rosuvastatin, as Rosuvastatin Calcium), Drug Identification Number (DIN): 02433125 p.29 (Date of Preparation: October 31, 2014). Available from, as of March 30, 2017: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60 or 80 mg/kg/day, the incidence of uterine polyps was statistically significantly increased only in females at the dose of 80 mg/kg/day. This dose produced a plasma AUC(0-24) value approximately 8 times higher (after correction for interspecies differences in protein binding) than the human plasma drug exposure after a 40 mg dose at steady-state. Increased incidences of polyps observed at 2, 20 and 60 mg/kg/day were not statistically different from the control group not exposed to rosuvastatin. The 60 mg/kg/day dose produced a plasma AUC(0-24) value approximately 5 times higher (after correction for interspecies differences in protein binding) than the mean human exposure after a 40 mg dose at steady-state. The occurrence of uterine polyps in old female rats is well-known and is considered benign tumors and lesions termed non-neoplastic in humans.
Health Canada; Product Monograph for Rosuvastatin Calcium Tablets (5 mg, 10 mg, 20 mg and 40 mg of Rosuvastatin, as Rosuvastatin Calcium), Drug Identification Number (DIN): 02433125 p.32 (Date of Preparation: October 31, 2014). Available from, as of March 30, 2017: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 107-week carcinogenicity study in mice given 10, 60, 200 or 400 mg/kg/day, the 400 mg/kg/day dose was poorly tolerated, resulting in early termination of this dose group. An increased incidence of hepatocellular carcinomas was observed at 200 mg/kg/day and an increase in hepatocellular adenomas was seen at 60 and 200 mg/kg/day. The dose of 200 mg/kg/day produced a plasma AUC(0-24) value approximately 37 times higher (after correction for interspecies differences in protein binding) than the mean human plasma drug exposure after a 40 mg dose at steady state. An increased incidence of hepatocellular tumors was not seen at 10 mg/kg/day. The 60 mg/kg/day dose produced a plasma AUC(0-24) value approximately 4.9 times higher (after correction for interspecies differences in protein binding) than the mean human plasma drug exposure after a 40 mg dose at steady state. These hepatocellular effects are known to occur in rodents treated with statins without evidence of similar effects in humans.
Health Canada; Product Monograph for Rosuvastatin Calcium Tablets (5 mg, 10 mg, 20 mg and 40 mg of Rosuvastatin, as Rosuvastatin Calcium), Drug Identification Number (DIN): 02433125 p.32 (Date of Preparation: October 31, 2014). Available from, as of March 30, 2017: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Rosuvastatin administration did not indicate a teratogenic effect in rats at
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
For more Non-Human Toxicity Excerpts (Complete) data for Rosuvastatin (11 total), please visit the HSDB record page.

11.1.14 Populations at Special Risk

The ACC/AHA cholesterol management guideline states that initiation of statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients older than 75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care. Therefore, the potential for an ASCVD risk reduction benefit, adverse effects, and drug interactions, along with patient preferences, must be considered before initiating statin therapy in patients older than 75 years of age. /Statins/
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1854
Rosuvastatin should be used with caution in patients who consume substantial amounts of alcohol and/or have a history of chronic liver disease. The drug is contraindicated in patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1865
Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86% (90 % confidence interval (CI), 51-130%) and 55 % (26-91%) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53% (25-88%) and 69% (37-108%) higher for atorvastatin, 23% (0-52%) and 12% (-0.9-39%) higher for simvastatin and 28% (5-56%) and 34% (10-64%) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.
Birmingham BK et al; Eur J Clin Pharmacol 71 (3): 341-55 (2015)
Crestor 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 Crestor during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Crestor may cause fetal harm when administered to pregnant women. Crestor should be discontinued as soon as pregnancy is recognized.
NIH; DailyMed. Current Medication Information for Crestor (Rosuvastatin Calcium Tablet, Film-Coated) (Updated: May 2016). Available from, as of March 30, 2017: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb0f3b5e-4bc6-41c9-66b9-6257e2513512
For more Populations at Special Risk (Complete) data for Rosuvastatin (7 total), please visit the HSDB record page.

11.1.15 Protein Binding

Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

11.2 Ecological Information

11.2.1 Environmental Fate / Exposure Summary

Rosuvastatin's production and administration as a medication may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 5.3X10-19 mm Hg at 25 °C indicates rosuvastatin will exist solely in the particulate phase in the atmosphere. Particulate-phase rosuvastatin will be removed from the atmosphere by wet and dry deposition. Rosuvastatin contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, rosuvastatin is expected to have very high mobility based upon an estimated Koc of 48. The estimated pKa1 of rosuvastatin is 4.0, indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Rosuvastatin is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation half-lives of 3.1 and 5.2 days were reported for rosuvastatin calcium in the Modified OECD 302B test suggesting that biodegradation of rosuvastatin may be an important environmental fate process in soil and water. However, <1% of rosuvastatin calcium was mineralized. If released into water, rosuvastatin is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. The estimated pKa1 indicates rosuvastatin will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to rosuvastatin may occur through inhalation and dermal contact with this compound at workplaces where rosuvastatin is produced or used. The general public is not likely to be exposed to rosuvastatin unless by direct medical treatment. (SRC)

11.2.2 Artificial Pollution Sources

Rosuvastatin's production and administration as an antilipemic(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1540 (2013)

11.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 48(SRC), determined from a structure estimation method(2), indicates that rosuvastatin is expected to have very high mobility in soil(SRC). The estimated pKa of rosuvastatin is 4.0(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize(SRC). Rosuvastatin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.3X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation half-lives of 3.1 and 5.2 days were reported for rosuvastatin calcium in the Modified OECD 302B test(5) suggesting that biodegradation of rosuvastatin may be an important environmental fate process in soil(SRC). However, <1% of rosuvastatin calcium was mineralized(5).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Dec 12, 2016: https://www2.epa.gov/tsca-screening-tools
(3) ACE; ACE and JChem acidity and basicity calculator. ACE UKY-4.0. 2005-2015. Marvin JS. ChemAxon. Available from, as of Dec 12, 2016: https://epoch.uky.edu/ace/public/pKa.jsp
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) AstraZeneca. Environmental Risk Assessment Data. Rosuvastatin calcium. Available from, as of Dec 13, 2016: https://www.astrazeneca.com/content/dam/az/our-company/Sustainability/Rosuvastatin-Calcium.pdf
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 48(SRC), determined from a structure estimation method(2), indicates that rosuvastatin is not expected to adsorb to suspended solids and sediment(SRC). The estimated pKa of 4.0(3) indicates rosuvastatin will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of -0.88(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation half-lives of 3.1 and 5.2 days were reported for rosuvastatin calcium in the Modified OECD 302B test(6) suggesting that biodegradation of rosuvastatin may be an important environmental fate process in water(SRC). However, <1% of rosuvastatin calcium was mineralized(6).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Dec 12, 2016: https://www2.epa.gov/tsca-screening-tools
(3) ACE; ACE and JChem acidity and basicity calculator. ACE UKY-4.0. 2005-2015. Marvin JS. ChemAxon. Available from, as of Dec 12, 2016: https://epoch.uky.edu/ace/public/pKa.jsp
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1540 (2013)
(6) AstraZeneca. Environmental Risk Assessment Data. Rosuvastatin calcium. Available from, as of Dec 13, 2016: https://www.astrazeneca.com/content/dam/az/our-company/Sustainability/Rosuvastatin-Calcium.pdf
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), rosuvastatin, which has an estimated vapor pressure of 5.3X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase rosuvastatin may be removed from the air by wet and dry deposition(SRC). Rosuvastatin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Dec 12, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

11.2.4 Environmental Biodegradation

AEROBIC: Rosuvastatin calcium, present at 1 and 45 mg/L, was 80% biodegraded in 4 weeks using in the Modified OECD 302B test. Half-lives of 3.1 and 5.2 days were reported at concentrations of 1 and 45 mg/L, respectively. However, <1% of the test compound was mineralized(1). /Rosuvastatin calcium/
(1) AstraZeneca. Environmental Risk Assessment Data. Rosuvastatin calcium. Available from, as of Dec 13, 2016: https://www.astrazeneca.com/content/dam/az/our-company/Sustainability/Rosuvastatin-Calcium.pdf
ANAEROBIC: Rosuvastatin calcium, present at 35 and 50 mg/L C was <5% biodegraded in 56 days in the ISO 11734 test(1). /Rosuvastatin calcium/
(1) AstraZeneca. Environmental Risk Assessment Data. Rosuvastatin calcium. Available from, as of Dec 13, 2016: https://www.astrazeneca.com/content/dam/az/our-company/Sustainability/Rosuvastatin-Calcium.pdf

11.2.5 Environmental Abiotic Degradation

Rosuvastatin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Rosuvastatin contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

11.2.6 Environmental Bioconcentration

An estimated BCF of 3 was calculated in fish for rosuvastatin(SRC), using a log Kow of -0.88(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1540 (2013)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Dec 12, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

11.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of rosuvastatin can be estimated to be 48(SRC). According to a classification scheme(2), this estimated Koc value suggests that rosuvastatin is expected to have very high mobility in soil. The estimated pKa1 of rosuvastatin is 4.0(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Dec 12, 2016: https://www2.epa.gov/tsca-screening-tools
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) ACE; ACE and JChem acidity and basicity calculator. ACE UKY-4.0. 2005-2015. Marvin JS. ChemAxon. Available from, as of Dec 12, 2016: https://epoch.uky.edu/ace/public/pKa.jsp
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
Atorvastatin (ATO), rosuvastatin (RST) and simvastatin (SIM) are commonly used drugs that belong to the statin family (lowering human blood cholesterol levels) and have been detected as contaminants in natural waters. Stability and removal of ATO, RST and SIM from spiked wastewater produced at the Al-Quds University campus were investigated. All three statins were found to undergo degradation in wastewater (activated sludge). The degradation reactions of the three drugs in wastewater at room temperature follow first-order kinetics with rate constants of 2.2X10-7/sec (ATO), 1.8X10-7/sec (RST) and 1.8X10-6/sec (SIM), which are larger than those obtained in pure water under the same conditions, 1.9X10-8/sec (ATO), 2.2X10-8/sec (RST) and 6.2X10-7/sec (SIM). Degradation products were identified by LC-MS and LC/MS/MS. The overall performance of the wastewater treatment plant (WWTP) installed in the Al-Quds University campus towards the removal of these drugs was assessed showing that more than 90% of spiked ATO, RST and SIM were removed. In order to evaluate the efficiency of alternative removal methods to replace ultra-filtration membranes, adsorption isotherms for the three statins were investigated using both activated carbon and clay-micelle complex as adsorbents. The batch adsorption isotherms for the three statins were found to fit the Langmuir equation, with a larger number of adsorption sites and binding affinity for micelle-clay composite compared with activated carbon and filtration experiments of the three statins and their corresponding metabolites demonstrated a more efficient removal by micelle-clay filters.
Sulaiman S et al; Environ Technol 36: 3232-42 (2015)
Mean Koc values of 1.7, 140, 68 and 130 were reported for rosuvastatin calcium, using sandy clay loam (pH 6.2), silty clay loam (pH5.0), clay loam (pH 6.5) and sandy loam (pH 6.20 soils, respectively(1). /Rosuvastatin calcium/
(1) AstraZeneca. Environmental Risk Assessment Data. Rosuvastatin calcium. Available from, as of Dec 13, 2016: https://www.astrazeneca.com/content/dam/az/our-company/Sustainability/Rosuvastatin-Calcium.pdf

11.2.8 Volatilization from Water / Soil

The estimated pKa1 of 4.0(1) indicates rosuvastatin will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). Rosuvastatin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.3X10-19 mm Hg(SRC), determined from a fragment constant method(2).
(1) ACE; ACE and JChem acidity and basicity calculator. ACE UKY-4.0. 2005-2015. Marvin JS. ChemAxon. Available from, as of Dec 12, 2016: https://epoch.uky.edu/ace/public/pKa.jsp
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Dec 12, 2016: https://www2.epa.gov/tsca-screening-tools

11.2.9 Effluent Concentrations

Rosuvastatin was detected in 36% of samples at an average concentration of 31.0 ng/L (max 979 ng/L) following EU monitoring of 90 wastewater treatment plant effluents conducted in 2010; detection limit = 10 ng/L(1).
(1) Loos R et al; Water Res 47(17): 6475-87 (2013)

11.2.10 Milk Concentrations

EXPERIMENTAL: It is not known whether rosuvastatin is excreted in human milk. Studies in lactating rats have demonstrated that rosuvastatin is secreted into breast milk at levels 3 times higher than that obtained in the plasma following oral gavage dosing.
Physicians Desk Reference. 59th ed. Thomson PDR. Montvale, NJ 2005.

11.2.11 Probable Routes of Human Exposure

Occupational exposure to rosuvastatin may occur through inhalation and dermal contact with this compound at workplaces where rosuvastatin is produced or used. The general public is not likely to be exposed to rosuvastatin unless by direct medical treatment. (SRC)

11.2.12 Body Burden

Distributed into milk in animals; not known whether rosuvastatin is distributed into milk in humans.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1657

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Thieme References

13.5 Chemical Co-Occurrences in Literature

13.6 Chemical-Gene Co-Occurrences in Literature

13.7 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 FDA Orange Book Patents

14.4 Chemical Co-Occurrences in Patents

14.5 Chemical-Disease Co-Occurrences in Patents

14.6 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Protein Bound 3D Structures

15.2 Chemical-Target Interactions

15.3 Drug-Drug Interactions

15.4 Drug-Food Interactions

Take with or without food. Co-administration with food does not affect absorption.

15.5 Pathways

16 Biological Test Results

16.1 BioAssay Results

17 Classification

17.1 MeSH Tree

17.2 NCI Thesaurus Tree

17.3 ChEBI Ontology

17.4 KEGG: ATC

17.5 KEGG: Target-based Classification of Drugs

17.6 KEGG: Drug Groups

17.7 WHO ATC Classification System

17.8 FDA Pharm Classes

17.9 ChemIDplus

17.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

17.11 ChEMBL Target Tree

17.12 UN GHS Classification

17.13 NORMAN Suspect List Exchange Classification

17.14 CCSBase Classification

17.15 EPA DSSTox Classification

17.16 FDA Drug Type and Pharmacologic Classification

17.17 PFAS and Fluorinated Organic Compounds in PubChem

17.18 EPA Substance Registry Services Tree

17.19 MolGenie Organic Chemistry Ontology

18 Information Sources

  1. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
    (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid
    https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=18372
  2. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  5. Therapeutic Target Database (TTD)
  6. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  7. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  8. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  9. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  10. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid
    https://echa.europa.eu/substance-information/-/substanceinfo/100.155.376
    7-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-(methyl-methylsulfonyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid
    https://echa.europa.eu/substance-information/-/substanceinfo/100.216.011
    (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid (EC: 627-028-1)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/159978
    7-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-(methyl-methylsulfonyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid (EC: 689-191-5)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/221268
  11. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  12. Hazardous Substances Data Bank (HSDB)
  13. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  14. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  15. ChEBI
  16. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  17. LiverTox
  18. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  19. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  20. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  21. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  22. DailyMed
  23. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  24. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  25. Drugs and Lactation Database (LactMed)
  26. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  27. EU Clinical Trials Register
  28. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  29. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  30. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    ROSUVASTATIN
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  31. Japan Chemical Substance Dictionary (Nikkaji)
  32. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  33. Kruve Lab, Ionization & Mass Spectrometry, Stockholm University
    rosuvastatin
  34. MassBank Europe
  35. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  36. Metabolomics Workbench
  37. NIPH Clinical Trials Search of Japan
  38. NLM RxNorm Terminology
    LICENSE
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  39. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  40. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  41. SpectraBase
  42. Springer Nature
  43. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  44. Wikidata
  45. Wikipedia
  46. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
    Hydroxymethylglutaryl-CoA Reductase Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68019161
  47. PubChem
  48. GHS Classification (UNECE)
  49. EPA Substance Registry Services
  50. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  51. PATENTSCOPE (WIPO)
  52. NCBI
CONTENTS