Crestor

Eat a low-fat, low-cholesterol diet. Be sure to follow all exercise and dietary recommendations made by your doctor or dietitian. You can also visit the National Cholesterol Education Program (NCEP) website for additional dietary information at http://www.nhlbi.nih.gov/health/public/heart/chol/chol_tlc.pdf.

Rosuvastatin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• constipation
• stomach pain
• dizziness
• difficulty falling asleep or staying asleep
• depression
• joint pain
• headache
• memory loss or forgetfulness
• confusion

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately or get emergency medical help:

:

• muscle pain, tenderness, or weakness
• lack of energy
• fever
• chest pain
• yellowing of the skin or eyes
• dark colored urine
• pain in the upper right part of the abdomen
• nausea
• extreme tiredness
• weakness
• unusual bleeding or bruising
• loss of appetite
• flu-like symptoms
• rash
• hives
• itching
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness

Rosuvastatin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Keep all appointments with your doctor and the laboratory. Your doctor may order lab tests during your treatment, especially if you develop symptoms of liver damage.

Before having any laboratory test, tell your doctor and the laboratory personnel that you are taking rosuvastatin.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Dosage Forms & Strengths

tablet

• 5mg
• 10mg
• 20mg
• 40mg

Hypercholesterolemia

Hypertriglyceridemia, hyperlipidemia, mixed dyslipidemia, slowing progression of atherosclerosis, primary dysbetalipoproteinemia

10-20 mg PO qDay initially; may titrate; not to exceed 40 mg/day

Dosage range: 5-40 mg/day

Homozygous familial hypercholesterolemia: Initiate with 20 mg PO qDay; may titrate; not to exceed 40 mg/day

Primary Prevention

Primary prevention of cardiovascular disease in individuals with no clinically evident heart disease but who are at risk because of combined effect of risk factors listed below

Approval based on JUPITER trial (Justification for the Use of statins in Prevention: an Intervention Trial Evaluation Rosuvastatin)

Initial: 10-20 mg PO qDay

Dosage range 5-40 mg/day

Cardiovascular disease

• Shown to reduce risk of stroke, MI, and arterial revascularization procedures (including CABG, bypass grafting of peripheral artery or carotid artery, and angioplasty or stent placement)

Risk factors

• Age (>50 yr in men; >60 yr in women), AND
• Elevated high-sensitivity C-reactive protein level (>2 mg/L), AND
• Presence of at least 1 additional cardiovascular risk factor (eg, high blood pressure, low HDL-C, smoking, family history of premature heart disease)

Dosing Considerations

Patients of Asian descent: Initiate with 5 mg/day

Coadministration with other lipid-lowering therapy: Consider dose reduction if combined with niacin or fenofibrate, because of increased risk for skeletal muscle effects

Coadministration with cyclosporine: Not to exceed 5 mg/day

Coadministration with gemfibrozil: Avoid if possible; if used together, do not exceed 10 mg/day

Coadministration with ritonavir, lopinavir/ritonavir, or atazanavir/ritonavir: Not to exceed 10 mg/day

Overdose management

• Adverse drug reactions from overdose may include peripheral neuropathy, diarrhea, increased K+, myopathy, rhabdomyolysis, acute renal failure, elevated LFTs, eye lens opacities
• Treatment is supportive

Dosing Modifications

Renal impairment

• Severe (CrCl <30 mL/min/1.73m²) and not on hemodialysis: Decrease starting dose to 5 mg PO qDay; not to exceed 10 mg PO qDay
• CrCl>30mL/min/1.73m²: Dose adjustment not necessary
• Active liver disease: Use is contraindicated
• Chronic alcoholic liver disease is known to increase rosuvastatin exposure; caution advised

Dosage Forms & Strengths

tablet

• 5mg
• 10mg
• 20mg
• 40mg

Heterozygous Familial Hypercholesterolemia (HeFH)

Indicated to reduce total-C, LDL-C, and ApoB levels in children and adolescents aged 8-17 yr if after an adequate trial of diet therapy the following findings are present: LDL-C >190 mg/dL, or >160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or ≥2 CVD risk factors

<8 years: Safety and efficacy not established

8 to <10 years: 5-10 mg PO qDay

10-17 years: 5-20 mg PO qDay; may adjust dose at intervals of at least 4 wk; not to exceed 20 mg/day

Homozygous Familial Hypercholesterolemia (HoFH)

Indicated to reduce LDL-C, Total-C, nonHDL-C and ApoB in children and adolescents aged 7 to 17 yr with homozygous familial hypercholesterolemia, either alone or with other lipid-lowering treatments (eg, LDL apheresis)

<7 years: Safety and efficacy not established

7-17 years: 20 mg PO qDay

Contraindications

Hypersensitivity

Active liver disease, elevated LFTs

Pregnancy, lactation

Cautions

Nonserious and reversible cognitive side effects may occur

Increased blood sugar and glycosylated hemoglobin (HbA1c) levels reported with statin intake; in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus

Use caution in patients who consume large amounts of ethanol or have a history of liver disease

Interrupt therapy if serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment

Measure liver enzymes before initiating and if signs or symptoms of liver injury occur

Consider lower initial dose (5 mg qDay) in patients with risk of myopathy

Increased risk of rhabdomyolysis, especially at highest approved dose of 40 mg/day; reserve highest dose only for patients who fail to achieve desired cholesterol level at 20 mg/day

Use 5 mg/day starting dose in people of Asian ancestry, who may build up higher drug levels and be at higher risk of myopathy

Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persists despite discontinuing statin

Discontinue if CK levels are markedly elevated

Hematuria and proteinuria reported without decrease in renal function; consider dosage reduction if unexplained hematuria and proteinuria persists

Rule out secondary causes of hyperlipidemia prior to initiating therapy

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Crestor is the brand name for rosuvastatin, a prescription drug used to treat high cholesterol levels.

Crestor is in a class of drugs known as statins, which slow the buildup of plaque in your arteries and reduce your levels of “bad” cholesterol (LDL or low-density lipoprotein) and triglycerides in the blood.

At the same time, Crestor increases HDL or high-density lipoprotein levels, also known as “good” cholesterol.

There is no generic form of Crestor currently available to consumers. The drug was approved by the Food and Drug Administration (FDA) in 2003 and is manufactured by AstraZeneca.

Your doctor may prescribe Crestor to lower your risk of stroke, heart attack, or other cardiac complications, which can occur in those who have diabetes, coronary heart disease, or other risk factors.

Using Crestor alone is not enough: You will also have to eat a healthy diet and make other lifestyle changes like exercising, quitting smoking, and maintaining a healthy weight.

Even if you make all of these lifestyle changes, it may still take up to four weeks before you get the full benefit of Crestor.

Crestor Warnings

People of Asian descent should be aware that they might absorb this drug at a faster rate than other people. As a result, your doctor might need to put you on a lower-than-normal starting dose.

In some rare cases, people using Crestor have developed a disorder in which muscle tissue breaks down, resulting in kidney failure.

This is more likely to happen if you are older or if you have kidney disease or an underactive thyroid (hypothyroidism) that is poorly controlled.

Let your doctor know if you drink two or more alcoholic beverages a day, have diabetes, a thyroid disorder, kidney or liver disease.

It’s important that you limit alcoholic beverages while taking Crestor since continued daily use of alcohol could increase your risk of developing liver problems.

Crestor and Pregnancy

The FDA has issues a black-box warning regarding the use of Crestor while you are pregnant because it could harm your fetus.

Let your doctor know if you are pregnant or might become pregnant while taking this medication.

It’s also not recommended that you take Crestor while breastfeeding, since it’s unknown if this medication will pass into your breast milk.

Crestor is a prescription medicine used to lower "bad" cholesterol (LDL-C), increase "good" cholesterol (HDL-C) and decrease triglycerides in your blood.

Crestor is part of the drug class:

• HMG CoA reductase inhibitors

If you take too much of this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• Store Crestor at room temperature, 68 to 77°F (20 to 25°C) and in a dry place.
• If your health care professional tells you to stop treatment or if your medicine is out of date, throw the medicine away.
• Keep Crestor and all medicines in a secure place and out of the reach of children.

Minimally (approximately 10%) metabolized by CYP2C9.1 Clearance not dependent on metabolism by CYP3A4 to a clinically important extent.1

Drugs Affecting Transport Systems

Substrate for organic anion transport protein (OATP) 1B1 and breast cancer resistance protein (BCRP).1 Concomitant use with drugs that inhibit these transport proteins potentially may increase plasma concentrations of rosuvastatin and increase risk of myopathy.1 Consult relevant prescribing information of such drugs when considering concomitant use.1

Specific Drugs

• Selectively and competitively inhibits HMG-CoA reductase, causing subsequent reduction in hepatic cholesterol synthesis.1 2 Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, non-HDL-cholesterol, apo B, and triglycerides; increases HDL-cholesterol concentrations.1

• Statins may slow progression of and/or induce regression of atherosclerosis in coronary and/or carotid arteries,113 114 115 116 117 118 119 120 121 122 123 modulate BP in hypercholesterolemic patients with hypertension,124 125 and possess anti-inflammatory activity.126 127

• Tell all of your health care providers that you take Crestor. This includes your doctors, nurses, pharmacists, and dentists.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Do not take more than what your doctor told you to take. Taking more than you are told may raise your chance of very bad side effects.
• Follow the diet and workout plan that your doctor told you about.
• Avoid or limit drinking alcohol to less than 3 drinks a day. Drinking too much alcohol may raise your chance of liver disease.
• Take antacids that have aluminum or magnesium in them at least 2 hours after taking this medicine.
• If you are of Asian descent, use Crestor with care. You could have more side effects.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking Crestor, call your doctor right away.
• Use birth control that you can trust to prevent pregnancy while taking this medicine.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Blood in the urine.
• Not able to pass urine or change in how much urine is passed.
• This medicine may cause muscle pain, tenderness, or weakness. Sometimes, a very bad muscle problem may happen that may lead to kidney problems. Rarely, deaths have happened in people who get these problems when taking drugs like this one. Call your doctor right away if you have muscle pain, tenderness, or weakness that is not normal (with or without fever or feeling out of sorts). Call your doctor right away if you have muscle signs that last after your doctor has told you to stop taking this medicine.
• Very bad and sometimes deadly liver problems have happened with Crestor (rosuvastatin). Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Crestor or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Crestor. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Hyperlipidemia and Mixed Dyslipidemia

Crestor is indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL‑C, and triglycerides and to increase HDL‑C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.

Pediatric Patients with Familial Hypercholesterolemia

Crestor is indicated as an adjunct to diet to:

Hypertriglyceridemia

Crestor is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

Crestor is indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).

Adult Patients with Homozygous Familial Hypercholesterolemia

Crestor is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL‑C, Total‑C, and ApoB in adult patients with homozygous familial hypercholesterolemia.

Slowing of the Progression of Atherosclerosis

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.

Primary Prevention of Cardiovascular Disease

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:

Limitations of Use

Crestor has not been studied in Fredrickson Type I and V dyslipidemias.

5 mg: Yellow, round, biconvex, coated tablets. Debossed “Crestor” and “5” on one side of the tablet.

10 mg: Pink, round, biconvex, coated tablets. Debossed “Crestor” and “10” on one side of the tablet.

20 mg: Pink, round, biconvex, coated tablets. Debossed “Crestor” and “20” on one side of the tablet.

40 mg: Pink, oval, biconvex, coated tablets. Debossed “Crestor” on one side and “40” on the other side of the tablet.

Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Crestor. These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Crestor 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 Crestor may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir [see Dosage and Administration (2) and Drug Interactions (7)]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing Crestor with colchicine [see Drug Interactions (7.7)].

Crestor therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Crestor therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Crestor.

Liver Enzyme Abnormalities

It is recommended that liver enzyme tests be performed before the initiation of Crestor, and if signs or symptoms of liver injury occur.

Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG‑CoA reductase inhibitors, including Crestor. 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 Crestor therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking Crestor versus 0.5% of patients treated with placebo.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Crestor, promptly interrupt therapy. If an alternate etiology is not found, do not restart Crestor.

Crestor should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [see Clinical Pharmacology (12.3)]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of Crestor [see Contraindications (4)].

Concomitant Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with Crestor because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and Crestor concomitantly, INR should be determined before starting Crestor and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Drug Interactions (7.4)].

Proteinuria and Hematuria

In the Crestor clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among Crestor treated patients. These findings were more frequent in patients taking Crestor 40 mg, when compared to lower doses of Crestor or comparator HMG‑CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on Crestor therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

Endocrine Effects

Increases in HbA1c and fasting serum glucose levels have been reported with HMG‑CoA reductase inhibitors, including Crestor. Based on clinical trial data with Crestor, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see Adverse Reactions (6.1)].

Although clinical studies have shown that Crestor alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if Crestor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

Cyclosporine

Cyclosporine increased rosuvastatin exposure (AUC) 7‑fold. Therefore, in patients taking cyclosporine, the dose of Crestor should not exceed 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1)and Clinical Pharmacology (12.3)].

Gemfibrozil

Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with Crestor and gemfibrozil should be avoided. If used together, the dose of Crestor should not exceed 10 mg once daily [see Clinical Pharmacology (12.3)].

Protease Inhibitors

Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure (AUC) up to threefold [see Table 4 – Clinical Pharmacology (12.3)]. For these protease inhibitors, the dose of Crestor should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors [see Dosage and Administration (2.4),Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Coumarin Anticoagulants

Crestor significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with Crestor. In patients taking coumarin anticoagulants and Crestor concomitantly, INR should be determined before starting Crestor and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Niacin

The risk of skeletal muscle effects may be enhanced when Crestor is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with Crestor [see Warnings and Precautions (5.1)].

Fenofibrate

When Crestor was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with Crestor [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with HMG‑CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing Crestor with colchicine [see Warnings and Precautions (5.1)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.

In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.

Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6‑month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.

Animal Toxicology and/or Pharmacology

Central Nervous System Toxicity

CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year.

Juvenile Toxicology Study

In a juvenile study, rats were dosed by oral gavage with 10 or 50 mg/kg/day from weaning for 9 weeks prior to pairing, throughout pairing and up to the day before necropsy for males or up to gestation day 7 for females. No effects on sexual development, testicular and epididymal appearance or fertility were observed at either dose level (2 times or up to 24 times the human exposure (AUC) at the maximum pediatric dose of 20 mg/day).

Use is contraindicated. Excreted into human milk: Yes (in low amounts) Comments: -This drug should not be used during breastfeeding due to the potential for serious adverse events in nursing infants and the concern over disruption of infant lipid metabolism.

LactMed Record Number

486

Last Revision Date

20131022

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Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.