Rosuvastatin is a selective, competitive, HMG-CoA reductase inhibitor. It potently reduces total and LDL cholesterol and lowers plasma triglycerides and apolipoprotein B (Apo-B). Because of its chemical structure binding sites and relatively greater hydrophilicity, it appears to better penetrate the hepatocyte and bind to HMG-CoA reductase with a higher affinity than other statins. In adult patients with primary hypercholesterolemia, dose-related LDL-reduction is 45% with 5 mg, 52% with 10mg, 55% with 20 mg, and 63% with 40 mg; doses of 5 to 40 mg/day lower triglycerides by 21% to 43%. Similar to other statins, rosuvastatin produces modest increases in HDL (8% to 12%). In a 12 week comparative trial in adult patients, 5 and 10 mg doses reduced LDL by 42% and 49%, compared with 28% for pravastatin and 37% for simvastatin. In another comparative trial, 12 weeks of rosuvastatin 5 and 10 mg reduced LDL by 46% and 50%, compared with 39% for atorvastatin 10 mg. Results from the ECLIPSE study demonstrated that more patients treated with rosuvastatin 40 mg, compared to atorvastatin 80 mg, for 24 weeks achieved the NCEP ATP III LDL-C goal of less than 100 mg/dL (83.6% vs. 74.6%; p less than 0.001). In children with heterozygous familial hypercholesterolemia (n = 176), 12 weeks of rosuvastatin doses of 5 mg, 10 mg, and 20 mg daily reduced LDL by 38%, 45%, and 50%, respectively and apolipoprotein B by 32%, 38%, and 41%, respectively. Rosuvastatin undergoes minimal hepatic metabolism and is expected to have less potential for hepatic CYP3A4 drug interactions than other statins. Also relative to other statins, a significant percentage (28%) is excreted renally. Cholesterol-lowering efficacy has been demonstrated in hypercholesterolemic patients with diabetes, peripheral vascular disease, and coronary heart disease. Investigations of intensive lipid-lowering with rosuvastatin 40 mg/day have demonstrated reduced progression of coronary and carotid atherosclerosis and significantly lower LDL-C concentrations (ASTEROID and METEOR trials). The SATURN trial reported no statistically significant difference between atorvastatin 80 mg once daily and rosuvastatin 40 mg once daily on the progression of atherosclerosis in high-risk patients measured by change from baseline in percent atheroma volume in a 40 mm or greater segment of the targeted coronary artery as assessed by intravascular ultrasound. There was, however, a statistically significant difference in total atheroma volume within the targeted coronary artery in favor of rosuvastatin. The Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, designed to assess rosuvastatin's affects on apparently healthy individuals with normal LDL but elevated C-reactive protein (CRP) concentrations, found a significantly reduced composite endpoint of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, or confirmed death from cardiovascular causes by 44% compared to individuals treated with placebo. Rosuvastatin also significantly reduced the risk of the secondary endpoint, the first occurrence of symptomatic venous thromboembolism, by 43% compared to placebo. A large retrospective study of adults demonstrated that continuation of statin therapy provides an ongoing reduction in all-cause mortality in patients with and without known coronary heart disease (CHD), with the greatest risk reduction among patients with a baseline LDL-C of 190 mg/dL or greater and patients initiated on higher efficacy statins (i.e., simvastatin, pravastatin, or lovastatin 80 mg/day; atorvastatin 20 mg/day or more; rosuvastatin 10 mg/day or more). Among patients with a proportion of days covered (PDC) of 90% or greater, determined by the number of statin prescriptions dispensed during the time between the first statin prescription and the end of follow up, there was a 45% and 51% lower mortality risk in the primary (patients without known CHD) and secondary (patients with known CHD) prevention groups, respectively, compared to patients with a PDC of 10% or greater. The mean length of follow up was 4 and 5 years in the primary and secondary prevention groups, respectively, with a maximum length of follow up of 9.5 years. The FDA approved rosuvastatin for various lipid disorders, including primary hypercholesterolemia, mixed dyslipidemia, and isolated hypertriglyceridemia, in August 2003. In November 2007, it received FDA approval for adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients. In February 2010, it was approved for the primary prevention of cardiovascular disease in patients with risk factors. In October 2009, it was approved for the treatment of heterozygous familial hypercholesterolemia in children and adolescents 10 to 17 years based on results from the Pediatric Lipid Reduction Trial of Rosuvastatin (PLUTO) study; in November 2015, this indication was expanded to include children as young as 8 years based on results from the hyperCholesterolaemia in cHildren and Adolescents taking Rosuvastatin OpeN label (CHARON) study. Rosuvastatin received expanded approval in pediatric patients as young as 7 years with homozygous familial hypercholesterolemia in May 2016.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May administer without regard to food. Food may decrease the rate of absorption by 20%, but does not affect the overall bioavailability.
-Tablets and capsules should be swallowed whole.
-Instruct patients not to take 2 doses of rosuvastatin within 12 hours of each other.
-Evening or morning administration does not affect rosuvastatin pharmacokinetics or cholesterol-lowering effects.
Oral Solid Formulations
Capsules (e.g., Ezallor) administration
-Capsules should not be crushed or chewed.
-Capsules may be opened and the granules emptied onto one teaspoon of applesauce or chocolate/vanilla flavored pudding. The mixture should be swallowed within 60 minutes and without chewing. Prepare just prior to administration; do not store for future use. Administer the entire dosage and discard any of the mixture that remains after administration.
-Nasogastric tube administration: For administration via nasogastric (NG) tube, the capsule may be opened and granules emptied into 60 mL catheter tipped syringe. Add 40 mL of water, replace the plunger, and shake vigorously for 15 seconds. It is acceptable if the granules begin to dissolve. Administer through the NG tube (16 French or greater). Flush NG tube with 60 mL of water following rosuvastatin administration. Prepare just prior to administration; do not store for future use. Administer the entire dosage. Use of other liquids not recommended.
Thyroid function abnormalities have been reported during clinical trials of rosuvastatin.
Amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease) has been reported to the FDA in a higher than expected number of patients taking statins, such as rosuvastatin. ALS is a progressive motor neuron disorder with symptoms such as difficulty walking or standing, difficulty with fine motor skills, atrophy of tongue and hand muscles, dysphagia, dysarthria, and muscle paralysis. Due to the seriousness of ALS and the extensive use of statins, FDA further examined data from 41 long-term controlled clinical trials. The results of the review showed no increased incidence of ALS in patients treated with a statin compared with placebo. Specifically, 9 of approximately 64,000 patients treated with a statin (4.2 cases per 100,000 patient-years) and 10 of approximately 56,000 patients treated with placebo (5 case per 100,000 patient-years) were diagnosed with ALS. FDA is examining the feasibility of performing additional epidemiologic studies to further examine the incidence and clinical course of ALS in patients taking statins.
Rosuvastatin can cause myopathy (muscle pain, muscle tenderness, or muscle weakness (myasthenia) associated with elevated creatine kinase (CK) levels) and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including rosuvastatin. Discontinue rosuvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK elevations may resolve if rosuvastatin is discontinued. Temporarily discontinue rosuvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain drugs (including other lipid lowering therapies), and higher rosuvastatin dosage. Individuals of Asian descent receiving rosuvastatin may be at higher risk of developing myopathy. Additionally, the risk of myopathy is greater with rosuvastatin 40 mg daily compared with lower rosuvastatin doses. During clinical trials, myalgia occurred in 1.9 to 12.7% of patients taking rosuvastatin. In the METEOR trial, increased serum creatine phosphokinase was observed in 2.6% of patients receiving rosuvastatin 40 mg compared to 0.7% of those receiving placebo. In a pediatric trial of boys and postmenarchal girls, elevations in serum creatine phosphokinase greater than 10 times the upper limit of normal were observed in 3% of children treated with rosuvastatin compared to no children treated with placebo. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Dipstick-positive proteinuria and microscopic hematuria were reported in rosuvastatin clinical studies. Renal failure (unspecified) has been reported in less than 1% of patients treated with rosuvastatin. In a comparative trial, rosuvastatin 40 mg/day has been associated with a higher frequency (1.3%) of renal-related adverse events (hematuria, proteinuria) versus 40 mg/day of pravastatin (0%), atorvastatin (0.4%), or simvastatin (0.8%). In an observational cohort study evaluating the post-marketing safety of rosuvastatin (5, 10, 20, 30, and 40 mg daily doses) in 11, 680 patients, proteinuria was observed at a rate of less than 0.1% in all patients regardless of dose and 0.4% of patients in the 40 mg/day group. The long-term consequences of these renal-related events are not known. Reduce the rosuvastatin dosage in patients who have unexplained persistent proteinuria or hematuria during routine urinalysis testing.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred with HMG-CoA reductase inhibitors, such as rosuvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Statin-induced IMNM is a rare event making it difficult to determine the true incidence of this adverse reaction; however, available literature reports a range of 1 to 3 of every 100,000 patients treated with an HMG-CoA reductase inhibitor develop IMNM. Based on the available data, patients with IMNM have myalgia with symmetrical and proximal weakness that occurs months to years after starting HMG-CoA reductase therapy and the myopathy persists or even progress following therapy discontinuation. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed. Discontinue rosuvastatin if IMNM is suspected.
Adverse GI effects reported during clinical trials of rosuvastatin compared to placebo include nausea (0 to 6.3% vs. 2.3 to 3.1%), constipation (2.1 to 4.7% vs. 2.4 to 3%), and abdominal pain (2.4% vs. 1.8%).
Although rare, severe hepatotoxicity may occur during HMG-CoA reductase inhibitor therapy. Hepatitis, jaundice, pancreatitis, and fatal and non-fatal hepatic failure have been reported with rosuvastatin. Liver function tests (LFTs) should be performed prior to initiation of therapy with rosuvastatin and then repeated as clinically indicated. Elevated hepatic transaminases have been reported in patients receiving HMG-CoA reductase inhibitors; these abnormalities were not associated with cholestasis and did not appear to be associated with treatment duration. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin, discontinue rosuvastatin. Rosuvastatin therapy has been associated with elevated hepatic enzymes greater than 3 times the upper limit of normal; in pooled analysis of placebo-controlled trials, the incidence was 1.1% in patients taking rosuvastatin compared to 0.5% of patients taking placebo. In the METEOR trial, 2.2% of patients receiving rosuvastatin 40 mg/day experienced an elevation in AST greater than 3 times the upper limit of normal. Elevations in transaminases, glutamyl transpeptidase, alkaline phosphatase, and bilirubin have been reported with rosuvastatin therapy. Additionally, in an observational cohort study evaluating the post-marketing safety of rosuvastatin, abnormalities of liver function tests occurred at a rate 2.5-fold higher for patients taking 40 mg daily compared with those taking 10 mg daily (2.71; 95% CI 1.53, 4.53).
CNS events reported during rosuvastatin therapy compared to placebo have included: asthenia (0.9% to 4.7% vs. 2.6%), headache (3.1 to 8.5% vs. 5 to 5.3%), and dizziness (4% vs. 2.8%). Rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with the use of statins. A review of available data by the FDA did not find an association between the event and a specific statin, statin dose, concomitant medication, or age of the patient. In general, post-marketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The cases did not appear to be associated with progressive or fixed dementia. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable. Depression, memory impairment (memory loss), and sleep disorders, including insomnia and nightmares, have been reported during postmarketing use of rosuvastatin.
Arthralgia has been reported during therapy with rosuvastatin. In clinical trials, arthralgia was reported in 3.8% to 10.1% of rosuvastatin patients vs. 3.2% to 7.1% of placebo-treated patients.
Elevated glycated hemoglobin, hyperglycemia, and new cases of diabetes mellitus have been reported in patients taking rosuvastatin. In the JUPITER trial, elevated glycated hemoglobin occurred more frequently in patients taking rosuvastatin compared to those receiving placebo (5.9% vs. 5.8%, respectively, p=0.001) as did physician-reported diabetes (3% vs. 2.4%, respectively, p=0.01). Increased hemoglobin A1C and fasting serum glucose (hyperglycemia) have been reported during therapy with HMG-CoA reductase inhibitors. A meta-analysis of 13 statin trials with 91,140 participants showed a 9% increase in the likelihood of the development of diabetes (OR 1.09; 95% CI 1.02 to 1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70 to 82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure) compared to patients with low diabetes risk (i.e., low BMI). Additionally, an analysis of the data from the Women's Health Initiative (WHI) trial found that statin use in postmenopausal women is associated with an increased risk of new-onset diabetes mellitus (multivariate-adjusted HR 1.48; 95% CI 1.38 to 1.59). No difference in the risk for diabetes between statins was detected in either analysis. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes should be considered when initiating rosuvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.
Hypersensitivity reactions, including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin therapy. Drug reaction with eosinophilia and systemic symptoms (DRESS) and lichen planus-like eruption (lichenoid drug eruption) have been reported in post-marketing surveillance with rosuvastatin.
An association between HMG-CoA reductase inhibitors (statins), including rosuvastatin, and peripheral neuropathy has been reported in the literature (case series, case-control studies, cohort studies). In a nested case-control study of a Danish population, the odds ratio for idiopathic peripheral neuropathy in 166 patients that ever or were currently taking a statin, was 3.7 (95% CI 1.8 to 7.6); similar results have been found in other population-based studies, although the number of patients studied was significantly smaller. Case reports and series indicate that the onset of neuropathy is typically greater than 1 year after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. The benefits of statin therapy far outweigh any risk of peripheral neuropathy; however, until more information is available, health care providers should be aware of this adverse effect. Peripheral neuropathy has been reported with post-marketing use of rosuvastatin.
HMG-CoA reductase inhibitors (statins), such as rosuvastatin, inhibit the synthesis of mevalonate and decrease Co-Enzyme Q-10 concentrations, which may lead to Co-Enzyme Q-10 deficiency. Supplementation with Co-Enzyme Q-10 may limit potential adverse reactions.
Interstitial lung disease has been reported with postmarketing use of rosuvastatin.
Exacerbation and induction of myasthenia gravis has been reported during treatment with statins, including rosuvastatin. In a review of adult patients enrolled at a neuromuscular disease clinic over a 4-year time period, 6 of 54 myasthenia gravis patients (11%) receiving statin therapy experienced worsening myasthenia gravis. In a disproportionality analysis of the World Health Organization's VigiBase pharmacovigilance database, 169 of 3,967 (4.2%) of adverse reactions with the term 'myasthenia gravis and related conditions' were related to statin therapy. The reporting odds ratio (ROR) of myasthenia gravis relative to all other adverse reactions was 2.66 [95% CI: 2.28, 3.1] for statin therapy. In addition, the ROR was greater than 1 and statistically significant for all individual statins except lovastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.
Thrombocytopenia has been reported with postmarketing use of rosuvastatin.
Rosuvastatin is contraindicated in patients with a known hypersensitivity to rosuvastatin or any component of the products. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin.
Rosuvastatin is contraindicated in patients with acute hepatic failure or decompensated cirrhosis. Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol (alcoholism) and/or have a history of hepatic disease. Increases in hepatic transaminases have been reported with rosuvastatin. In most cases, increases in hepatic transaminases occurred soon after initiation, were transient, were not associated with symptoms, and resolved or improved on continued therapy or after temporary discontinuation of therapy. In a pooled analysis of placebo-controlled trials, increases in serum transaminases of more than 3 times the upper limit of normal occurred in 1.1% of patients receiving rosuvastatin versus 0.5% of patients receiving placebo. Marked persistent increases in hepatic transaminases have also occurred with rosuvastatin. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. Consider assessing liver enzyme tests prior to initiation of rosuvastatin and repeat as clinically indicated thereafter. Elevated hepatic transaminases have been reported in patients receiving HMG-CoA reductase inhibitors; these abnormalities were not associated with cholestasis and did not appear to be associated with treatment duration. After extensive data review, the FDA concluded that the risk of serious liver injury is very low and routine periodic monitoring of liver enzymes has not been effective in detection or prevention of serious hepatic injury. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin, discontinue rosuvastatin.
Rosuvastatin can cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK) levels) and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including rosuvastatin. Discontinue rosuvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK elevations may resolve if rosuvastatin is discontinued. Temporarily discontinue rosuvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain drugs (including other lipid lowering therapies), and higher rosuvastatin dosage (i.e., higher risk with 40 mg daily compared to lower doses). Additionally, individuals of Asian descent receiving rosuvastatin may be at higher risk of developing myopathy. Since rosuvastatin undergoes minimal hepatic metabolism, the potential for drug interactions is expected to be less than with 'statins' metabolized by CYP3A4 isoenzymes such as atorvastatin, cerivastatin, lovastatin, and simvastatin. Rosuvastatin should be used with caution in patients with pre-existing significant renal impairment who are generally at a higher risk of developing rhabdomyolysis during therapy with HMG-CoA reductase inhibitors. Patients receiving the highest rosuvastatin dosage of 40 mg/day were found to have an increased frequency of hematuria and proteinuria (1.3%) compared to those on lower dosages or other HMG CoA-reductase inhibitors. In patients who have unexplained persistent proteinuria or hematuria during routine urinalysis testing, reduce the rosuvastatin dosage. Relative to other statins, a significant percentage (28%) of rosuvastatin is excreted renally. Rosuvastatin serum concentrations are increased approximately 3-fold in patients with severe renal impairment (i.e., creatinine clearance or CrCl less than 30 mL/minute not on hemodialysis) and thus a lower rosuvastatin daily dosage is recommended for these patients. Hemodialysis does not appreciably remove the drug. Inform patients of the increased risk of myopathy and rhabdomyolysis when starting or increasing the dosage of rosuvastatin. Instruct patients to promptly report unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever.
Use caution in prescribing rosuvastatin to Asian patients. Pharmacokinetic studies show an approximate 2-fold elevation in median exposure in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore compared with White patients residing in North America and Europe. The contribution of environmental and genetic factors to the difference observed has not been determined. However, these increases should be considered when making rosuvastatin dosing decisions for Asian patients of Japanese and Chinese ancestry and consider lower starting and maximum doses.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred with HMG-CoA reductase inhibitors, such as rosuvastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Statin-induced IMNM is a rare event making it difficult to determine the true incidence of this adverse reaction; however, available literature reports a range of 1 to 3 of every 100,000 patients treated with an HMG-CoA reductase inhibitor develop IMNM. Based on the available data, patients with IMNM have myalgia with symmetrical and proximal weakness that occurs months to years after starting HMG-CoA reductase therapy and the myopathy persists or even progress following therapy discontinuation. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed. Discontinue rosuvastatin if IMNM is suspected.
If rosuvastatin is initiated in a patient with diabetes, increased monitoring of blood glucose control may be warranted. Increased hemoglobin A1C, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Optimization of lifestyle measures, including regular exercise, maintaining a healthy body weight and making healthy food choices are recommended. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes mellitus should be considered when initiating rosuvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established. Although an analysis of participants from the JUPITER trial found an increased incidence of developing diabetes in patients allocated to rosuvastatin compared to placebo (270 reports of diabetes vs. 216 in the placebo group; HR 1.25, 95% CI 1.05 to 1.49, p = 0.01), the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard even in patients at high risk for developing diabetes (i.e., patients with 1 or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI 30 kg/m2 or more, or A1C greater than 6%). In patients at high risk for developing diabetes, treatment with rosuvastatin was associated with a 39% reduction in the primary endpoint (composite of non-fatal myocardial infarction, non-fatal stroke, unstable angina or revascularization, and cardiovascular death) (HR 0.61, 95% CI 0.47 to 0.79, p = 0.0001), nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, CI 0.39 to 1.06, p = 0.08) and total mortality (HR 0.83, CI 0.64 to 1.07, p = 0.15), and a 28% increase in diabetes (HR 1.28, CI 1.07 to 1.54, p = 0.01). In patients with no major diabetes risk factor, treatment with rosuvastatin was associated with a 52% reduction in the primary endpoint (HR 0.48, 95% CI 0.33 to 0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, CI 0.21 to 1.03, p = 0.05) and total mortality (HR 0.78, CI 0.59 to 1.03, p = 0.08), and no increase in diabetes (HR 0.99, CI 0.45 to 2.21, p = 0.99). For those at high risk for developing diabetes, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In those without major risk factors, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.
Rosuvastatin therapy should be discontinued once pregnancy is identified in most patients. Alternatively, consider the ongoing therapeutic needs of the individual patient. Based on the mechanism of action, rosuvastatin may cause fetal harm when administered to pregnant patients due to decreases in the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol. Cholesterol and other products of cholesterol biosynthesis are important for fetal development including synthesis of steroids and cell membranes. Treatment of hyperlipidemia during pregnancy is not generally necessary as atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have minimal impact on the outcome of long-term therapy of primary hypercholesterolemia. The U.S. Food and Drug Administration (FDA) completed a review of data from case series, prospective and retrospective observational cohort studies over decades of statin use in pregnant patients and concluded that these studies have not identified a drug-associated risk of major congenital malformations associated with statin use during pregnancy. In a Medicaid cohort linkage study of 1,152 statin-exposed pregnant women, no significant teratogenic effects were observed following maternal statin use during the first trimester of pregnancy after adjusting for potential confounders (i.e., maternal age, diabetes mellitus, hypertension, obesity, alcohol use, and tobacco use); the relative risk (RR) of congenital malformations was 1.07 (95% confidence interval (CI), 0.85 to 1.37). In addition, after accounting for confounders, there were no statistically significant increases in organ-specific malformations. In the study, statin treatment was started prior to pregnancy and was discontinued within the first trimester after pregnancy was detected in a majority of patients. In another cohort study of 469 patients who were dispensed statins during pregnancy, it was determined that there was no increase in congenital anomalies after adjustment for maternal age and comorbidities; however, statin use was associated with an increased risk of preterm labor (RR, 1.99 [95% CI, 1.46 to 2.71]) and low birth weight (RR, 1.51 [95% CI, 1.05 to 2.16]). In a published, retrospective cohort study of 281 statin-exposed pregnant women, patients on statin therapy had a miscarriage rate of 25% compared to 21% for pregnant women not on statin therapy (n = 2,643); adjusted hazard ratio was 1.64 (95% CI, 1.1 to 2.46). The FDA also re-reviewed non-clinical, animal data statin development programs and concluded that statins have a limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during embryofetal development during the pre- and post-natal period. Decreased fetal body weight, delayed ossification, and decreased pup survival were observed in pregnant rats administered rosuvastatin doses 10 to 12 times the maximum recommended human dose (MRHD). In pregnant rabbits administered rosuvastatin doses equivalent to the MRHD of 40 mg/day, a decrease in fetal viability and maternal mortality was observed. Rosuvastatin has been shown to cross the placenta in both rats and rabbits. Overall, available data have not identified a drug-associated risk of major congenital malformations, but published data are insufficient to determine if there is a drug-associated risk of miscarriage. Advise pregnant patients and patients of child-bearing potential of the potential risk of statin therapy to the fetus and the importance of informing their health care provider of known or suspected pregnancy.
Rosuvastatin is not recommended for use during breast-feeding. Limited data from case reports in published literature indicate that rosuvastatin is present in human milk. There is no information on the effects of rosuvastatin on the breastfed infant or the effects of the drug on milk production. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway. Based on the mechanism of action of rosuvastatin, there is potential for development of serious adverse reactions in a breastfed infant. Advise patients that breastfeeding is not recommended during treatment with rosuvastatin. If pharmacotherapy for hypercholesterolemia is necessary in the nursing mother, an alternative agent such as a nonabsorbable resin (cholestyramine, colesevelam, or colestipol) may be considered. These agents do not enter the bloodstream and will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.
Since advanced age (65 years or more) is a predisposing risk factor for myopathy and/or rhabdomyolysis, rosuvastatin should be prescribed with caution in the geriatric patient. Use cautious dose selection for geriatric patients due to greater frequency of decreased hepatic, renal, or cardiac function. During clinical trials, no significant differences in rosuvastatin safety or efficacy between older and younger adult patients were identified. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, HMG-CoA reductase inhibitors may impair liver function, and liver function monitoring should occur consistent with individual manufacturer recommendations (e.g., baseline, 12 weeks after initiation, after any dose increase, and periodically thereafter). HMG-CoA reductase inhibitors may cause myalgia, myopathy, and rhabdomyolysis that can precipitate kidney failure, particularly in combination with other cholesterol-lowering medications. Monitor geriatric patients receiving rosuvastatin for increased risk of myopathy.
The safe and effective use of rosuvastatin tablets have not been established in children and infants younger than 8 years of age with heterozygous familial hypercholesterolemia, younger than 7 years of age with homozygous hypercholesterolemia, or in pediatric patients with other types of hyperlipidemia. Safety and efficacy of rosuvastatin capsules have not been established in pediatric patients. During clinical trials, there was no detectable effect of rosuvastatin on growth, body mass index, or sexual maturation in children and adolescents older than 10 years. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children are not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8 to 10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.
Exacerbation and induction of myasthenia gravis have been reported during treatment with statins, including rosuvastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.
For the treatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control:
-for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglyceride concentrations, and to increase HDL-cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson types IIa or IIb); or to treat Fredrickson Type IV (hypertriglyceridemia, increased VLDL); or to treat primary dysbetalipoproteinemia (Type III hyperlipoproteinemia):
Oral dosage (rosuvastatin tablets):
Adults: The usual starting dose is 10 mg PO once daily. A lower starting dose of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL-reductions, patients with CrCl less than 30 mL/minute, or patients at higher risk for myopathy. For Asian patients, consider the lower starting dose of 5 mg PO once daily. The overall dosage range is 5 to 40 mg PO once daily. Doses of 5 mg, 10 mg, 20 mg, and 40 mg PO per day reduce LDL-cholesterol by 45%, 52%, 55%, and 63%, respectively. A dosage of 40 mg/day is associated with a higher risk of myopathy and should be reserved for patients who require further LDL-reduction after receiving 20 mg/day. The manufacturer originally intended to seek approval for an 80 mg dose; however, 2 patients developed renal toxicity while receiving this dose. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of hypertriglyceridemia or primary dysbetalipoproteinemia (Type III hyperlipoproteinemia):
Oral dosage (rosuvastatin capsules):
Adults: The usual starting dose is 10 mg to 20 mg PO once daily. A lower starting dose of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL-reductions, patients with CrCl less than 30 mL/minute, or patients at higher risk for myopathy. For Asian patients, consider the lower starting dose of 5 mg PO once daily. The overall dosage range is 5 to 40 mg PO once daily. A dosage of 40 mg/day is associated with a higher risk of myopathy and should be reserved for patients who have not reached their LDL-C goal with 20 mg/day. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the reduction of total cholesterol, LDL-cholesterol, nonHDL-cholesterol, and apolipoprotein B concentrations in patients with homozygous familial hypercholesterolemia (HoFH):
Oral dosage (rosuvastatin tablets):
Adults: The usual starting dose is 20 mg PO once daily. For Asian patients, consider the lower starting dose of 5 mg PO once daily. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Rosuvastatin may be used as an adjunct to other lipid-lowering therapy (e.g., LDL apheresis) when available. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 7 to 17 years: 20 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (rosuvastatin capsules):
Adults: The usual starting dose is 20 mg PO once daily. For Asian patients, consider the lower starting dose of 5 mg PO once daily. Maximum dose is 40 mg once daily and used in patients unable to achieve LDL-C goals with 20 mg/day. Adjust dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Rosuvastatin may be used as monotherapy or an adjunct to other lipid-lowering therapy (e.g., LDL apheresis) when available. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the reduction of total cholesterol, LDL-cholesterol, and apolipoprotein B concentrations in pediatric patients with heterozygous familial hypercholesterolemia (HeFH):
NOTE: Rosuvastatin is indicated for patients with HeFH who, after an adequate trial of diet therapy, have LDL-C higher than 190 mg/dL or LDL-C higher than 160 mg/dL and have a positive family history of premature cardiovascular disease or two or more other CVD risk factors.
Oral dosage (rosuvastatin tablets):
Children and Adolescents 10 to 17 years: 5 to 20 mg PO once daily is the usual dosage range. Individualize dosage based on the goals of therapy. Dosage adjustments should be made at intervals of 4 weeks or more. Doses above 20 mg/day PO have not been studied in this population. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 8 to 9 years: 5 to 10 mg PO once daily is the usual dosage range. Individualize dosage based on the goals of therapy. Dosage adjustments should be made at intervals of 4 weeks or more. Doses above 10 mg/day PO have not been studied in this population. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for slowing the progression of atherosclerosis (e.g., carotid, coronary):
Oral dosage (rosuvastatin tablets):
Adults: The usual starting dose is 10 mg PO once daily. A lower starting dosage of 5 mg PO once daily may be initiated in patients requiring less aggressive LDL-reductions, patients with CrCl less than 30 mL/minute, or patients at higher risk for myopathy. For Asian patients, consider the lower starting dose of 5 mg once daily. The overall dosage range is 5 to 40 mg PO once daily. Doses of 5 mg, 10 mg, 20 mg, and 40 mg per day reduce LDL-cholesterol by 45%, 52%, 55%, and 63%, respectively. Intensive lipid-lowering with 40 mg once daily has been shown to reduce the progression of carotid and coronary atherosclerosis in clinical trials (ASTEROID and METEOR studies). However, 40 mg/day is associated with a higher risk of myopathy and should be reserved for patients who require further LDL-reduction after receiving 20 mg/day. Adjust the initial dosage based on serum lipid measurements obtained at 2 to 4-week intervals. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For primary prevention of cardiovascular disease including myocardial infarction prophylaxis and stroke prophylaxis, and to reduce the risk of arterial revascularization procedures in patients without evidence of coronary heart disease but who have risk factors for cardiovascular disease:
NOTE: Increased risk of cardiovascular disease is based on age (50 years and older in men and 60 years and older in women), elevated C-reactive protein concentrations (greater than or equal to 2mg/L), and the presence of at least one additional cardiovascular disease risk factor (e.g.,hypertension, low HDL-C concentrations, smoking, or family history of premature coronary heart disease).
Oral dosage (rosuvastatin tablets):
Adults: The usual starting dose is 10 to 20 mg PO daily, with a dose range of 5 to 40 mg PO daily. For Asian patients, consider the lower starting dose of 5 mg PO once daily. Dosage adjustments should be made at 2 to 4-week intervals to achieve target goals for LDL-cholesterol. The dose used in the JUPITER study was 20 mg PO once daily. JUPITER was a randomized, double-blind, placebo-controlled multicenter trial assessing 17,802 men and women with LDL-C concentrations less than 130 mg/dL and C-reactive protein concentrations (CRP) greater than or equal to 2 mg/L. Patients were followed for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the reduction of cardiovascular mortality* after acute coronary syndromes (ACS)*, including acute myocardial infarction, STEMI*, acute myocardial infarction, NSTEMI*, and unstable angina*:
Oral dosage:
Adults: 20 or 40 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In persons with clinical atherosclerotic coronary vascular disease (ASCVD), reduction in LDL-C should be targeted with high-intensity or maximally-tolerated statin dosing unless contraindicated. High-intensity dosing aims to reduce LDL-C by 50% or more.
Maximum Dosage Limits:
-Adults
40 mg/day PO.
-Geriatric
40 mg/day PO.
-Adolescents
20 mg/day PO (rosuvastatin tablets). Safety and efficacy of rosuvastatin capsules have not been established.
-Children
7 to 12 years: 20 mg/day PO (rosuvastatin tablets). Safety and efficacy of rosuvastatin capsules have not been established.
1 to 6 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Not recommended in patients with hepatic disease (see Contraindications).
Patients with Renal Impairment Dosing
CrCl 30 ml/min or greater: No dosage adjustment needed.
CrCl less than 30 ml/min: Initially, 5 mg PO once daily for patients not receiving dialysis. Maximum dosage is 10 mg PO once daily. Rosuvastatin serum concentrations are increased approximately 3-fold in patients with severe renal impairment (CrCl less than 30 ml/min) vs. patients with normal renal function.
Intermittent hemodialysis
Until further data are available for hemodialysis patients, it would be prudent to initiate dosage at the lower end of the dosage range (e.g., 5 mg PO once daily), and adjust dosage to attain target LDL and lipid goals. Although the manufacturer does not provide dosage adjustment recommendations for patients receiving hemodialysis, rosuvastatin serum concentrations are increased by approximately 50% in patients receiving hemodialysis vs. patients with normal renal function. According to the manufacturer, hemodialysis does not significantly enhance the clearance of rosuvastatin.
*non-FDA-approved indication
Acalabrutinib: (Moderate) Coadministration of acalabrutinib and rosuvastatin may increase rosuvastatin exposure and increase the risk of rosuvastatin toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Rosuvastatin is a BCRP substrate.
Amoxicillin; Clarithromycin; Omeprazole: (Major) The lowest dose of rosuvastatin should be considered if coadministered with clarithromycin. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and rosuvastatin. Rosuvastatin is not extensively metabolized by CYP3A4, a mechanism by which several other statins have been reported to interact with clarithromycin.The mechanism may be an an effect on OATP1B1. Rosuvastatin is an OATP1B1 substrate. Monitor for clinical effectiveness of rosuvastatin and for potential myopathy.
Antacids: (Moderate) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Aprepitant, Fosaprepitant: (Minor) Use caution if rosuvastatin and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of rosuvastatin. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Rosuvastatin is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Atazanavir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with atazanavir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Atazanavir; Cobicistat: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with atazanavir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
Calcium Carbonate: (Moderate) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Calcium Carbonate; Risedronate: (Moderate) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Calcium Carbonate; Simethicone: (Moderate) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Calcium; Vitamin D: (Moderate) While not specifically reported with calcium carbonate, antacids (aluminum hydroxide; magnesium hydroxide combination) have been shown to reduce rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Capmatinib: (Moderate) Do not exceed a rosuvastatin dose of 10 mg once daily if concomitant use of capmatinib is necessary. Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a BCRP substrate and capmatinib is a BCRP inhibitor. Coadministration with capmatinib increased rosuvastatin exposure more than 2.1- fold.
Cimetidine: (Moderate) Use HMG-CoA reductase inhibitors with caution with concomitant drugs that may decrease the levels or activity of endogenous steroids, such as cimetidine. Evaluate patients with signs and symptoms of endocrine dysfunction appropriately. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production.
Clarithromycin: (Major) The lowest dose of rosuvastatin should be considered if coadministered with clarithromycin. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and rosuvastatin. Rosuvastatin is not extensively metabolized by CYP3A4, a mechanism by which several other statins have been reported to interact with clarithromycin.The mechanism may be an an effect on OATP1B1. Rosuvastatin is an OATP1B1 substrate. Monitor for clinical effectiveness of rosuvastatin and for potential myopathy.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and rosuvastatin, a substrate of OAT protein (OATP), may result in altered clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OATP substrates.
Cobicistat: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP.
Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
Cyclosporine: (Major) Do not exceed a rosuvastatin dose of 5 mg once daily when coadministered with cyclosporine. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1) and breast cancer resistance protein (BCRP) and cyclosporine is an inhibitor of these transporters. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. The rosuvastatin AUC was increased 7-fold in the presence of cyclosporine.
Daclatasvir: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
Daptomycin: (Major) Temporarily suspend HMG-CoA reductase inhibitors in patients taking daptomycin as cases of rhabdomyolysis have been reported with concomitant use. Both agents can cause myopathy and rhabdomyolysis when given alone and the risk may be increased when given together.
Darolutamide: (Major) Do not exceed a rosuvastatin dose of 5 mg once daily when coadministered with doralutamide. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter breast cancer resistance protein (BCRP) and OATP1B1/3; darolutamide is a BCRP and OATP1B1/3 inhibitor. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Darunavir: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicistat.
Darunavir; Cobicistat: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicistat.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicistat.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen.
Desogestrel; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Drospirenone; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Elacestrant: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with elacestrant. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and elacestrant is a BCRP inhibitor. Concomitant administration increased overall exposure of rosuvastatin by 1.2 fold.
Elagolix: (Moderate) Monitor for a decrease in rosuvastatin efficacy during concomitant use with elagolix and adjust the rosuvastatin dose as appropriate. Concomitant use has been observed to decrease rosuvastatin overall exposure by 40%.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for a decrease in rosuvastatin efficacy during concomitant use with elagolix and adjust the rosuvastatin dose as appropriate. Concomitant use has been observed to decrease rosuvastatin overall exposure by 40%.
Elbasvir; Grazoprevir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with elbasvir; grazoprevir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for rosuvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of rosuvastatin. Rosuvastatin is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3.
Eltrombopag: (Moderate) Use caution and monitor for signs of rosuvastatin toxicity if this drug is coadministered with eltrombopag. In clinical trials, a 50% dose reduction of rosuvastatin was recommended. Eltrombopag is an inhibitor of OATP1B1 and BCRP, and rosuvastatin is a substrate of both of these transporters. In a clinical study, administration of a single dose of rosuvastatin with eltrombopag increased plasma rosuvastatin AUC by 55% and the Cmax by 103%.
Eluxadoline: (Moderate) Close monitoring for adverse effects, such as rhabdomyolysis and myopathy, is advised when eluxadoline is administered concurrently with rosuvastatin. Eluxadoline is an inhibitor of the organic anion-transporting peptide (OATP1B1) and the breast cancer resistance protein (BCRP); rosuvastatin is a substrate of both transporters. Use of these drugs together results in a 40% increase in the exposure (AUC) and a 18% increase in the maximum plasma concentration (Cmax) of rosuvastatin. Administer the lowest effect rosuvastatin dose and monitor for adverse effects.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Moderate) Caution is warranted when elvitegravir is administered with rosuvastatin as there is a potential for decreased rosuvastatin concentrations. Alternatively, when elvitegravir is boosted with cobicistat, the concentration of rosuvastatin may be increased due to inhibition of OATP by cobicistat. In one pharmacokinetic study, the Cmax and AUC of rosuvastatin were increased by 89% and 38%, respectively, when given concurrently with cobicistat and elvitegravir. Patients may experience a decreased antilipemic effect elvitegravir and rosuvastatin are coadministered. If elvitegravir is boosted with cobicistat, patients may be at increased risk for side effects of rosuvastatin. Rosuvastatin is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Moderate) Caution is warranted when elvitegravir is administered with rosuvastatin as there is a potential for decreased rosuvastatin concentrations. Alternatively, when elvitegravir is boosted with cobicistat, the concentration of rosuvastatin may be increased due to inhibition of OATP by cobicistat. In one pharmacokinetic study, the Cmax and AUC of rosuvastatin were increased by 89% and 38%, respectively, when given concurrently with cobicistat and elvitegravir. Patients may experience a decreased antilipemic effect elvitegravir and rosuvastatin are coadministered. If elvitegravir is boosted with cobicistat, patients may be at increased risk for side effects of rosuvastatin. Rosuvastatin is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
Enasidenib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporters OATP1B1/3 and BCRP and enasidenib is an OATP1B1/3 and BCRP inhibitor. Coadministration of rosuvastatin after multiple doses of enasidenib increased rosuvastatin Cmax by 366% and AUC by 244%.
Encorafenib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with encorafenib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of OATP1B1/3 and BCRP; encorafenib is an OATP1B1/3 and BCRP inhibitor.
Erythromycin: (Minor) Erythromycin is generally associated with an increased risk of myopathy with HMG-CoA reductase inhibitors. This interaction is likely due to CYP3A4 inhibition of statins which are CYP3A4 substrates; however, rosuvastatin is not substantially metabolized, and is less likely to be significantly affected by CYP3A4 inhibitors such as erythromycin. However, other mechanisms, such as an effect on OATP1B1, may be involved. Rosuvastatin is an OATP1B1 substrate. Coadministration of a single dose of rosuvastatin (80 mg) with erythromycin results in 31% and 20% decrease in Cmax and AUC of rosuvastatin, respectively. The clinical significance of this interaction has not been established, monitor for effectiveness of rosuvastatin and for myopathy and adjust treatment as clinically indicated.
Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Ethinyl Estradiol; Norelgestromin: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Ethinyl Estradiol; Norgestrel: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.1 to 1.3-fold increase in the AUC and maximal concentrations of norgestrel. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of norgestrel, such as breast tenderness, nausea, headache, or fluid retention. (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Etonogestrel; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Etravirine: (Moderate) Concomitant use of etravirine and rosuvastatin has no effect on the serum concentration of rosuvastatin; however, the risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors.
Febuxostat: (Moderate) Do not exceed a rosuvastatin dose of 20 mg once daily if concomitant use of febuxostat is necessary. Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. Coadministration with febuxostat increased rosuvastatin exposure more than 1.9-fold.
Fenofibrate: (Moderate) Clinical practice guidelines state the concurrent use of fenofibrate and rosuvastatin is reasonable and preferred over gemfibrozil if statin/fibrate combination therapy is indicated. However, because combination therapy increases the risk of myopathy, caution is advised.
Fenofibric Acid: (Moderate) Clinical practice guidelines state the concurrent use of fenofibric acid and rosuvastatin is reasonable and preferred over gemfibrozil if statin/fibrate combination therapy is indicated. However, because combination therapy increases the risk of myopathy, caution is advised.
Fosamprenavir: (Major) Fosamprenavir increases rosuvastatin plasma concentrations. If these drugs are to be coadministered, use the lowest possible dose of rosuvastatin, or consider treatment with an alternative HMG-CoA reductase inhibitor such as fluvastatin or pravastatin.
Fostamatinib: (Moderate) Do not exceed a rosuvastatin dose of 20 mg once daily if concomitant use of fostamatinib is necessary. Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a BCRP substrate and fostamatinib is a BCRP inhibitor. Coadministration with fostamatinib increased rosuvastatin exposure more than 2-fold.
Fostemsavir: (Moderate) Use the lowest possible starting dose for rosuvastatin when administered concurrently with fostemsavir and monitor for signs of rosuvastatin-associated adverse events, such as rhabdomyolysis. Use of these drugs together increases the systemic exposure of rosuvastatin. Rosuvastatin is a substrate for the transporters OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
Futibatinib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with futibatinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and futibatinib is a BCRP inhibitor.
Gemfibrozil: (Major) Avoid concomitant use of gemfibrozil and rosuvastatin due to the increased risk of myopathy and rhabdomyolysis. If coadministration cannot be avoided, initiate rosuvastatin at a reduced dosage of 5 mg once daily; do not exceed a rosuvastatin dosage of 10 mg once daily. Clinical practice guidelines state the concurrent use of gemfibrozil and rosuvastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and gemfibrozil therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Gilteritinib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with gilteritinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and gilteritinib is a BCRP inhibitor.
Glecaprevir; Pibrentasvir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with glecaprevir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the drug transporters OATP1B1, OATP1B3, and BRCP; glecaprevir is an inhibitor of these transporters. In drug interaction studies, coadministration of rosuvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of rosuvastatin. (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with pibrentasvir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the drug transporters OATP1B1, OATP1B3, and BRCP; pibrentasvir is an inhibitor of these transporters. In drug interaction studies, coadministration of rosuvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of rosuvastatin.
Itraconazole: (Moderate) Itraconazole modestly increases the AUC of rosuvastatin by 28% and 39% in healthy volunteers receiving 80 mg and 10 mg rosuvastatin, respectively. A potential mechanism for this interaction is inhibition of the breast cancer resistance protein (BCRP) by itraconazole; rosuvastatin is a BCRP substrate.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) The lowest dose of rosuvastatin should be considered if coadministered with clarithromycin. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and rosuvastatin. Rosuvastatin is not extensively metabolized by CYP3A4, a mechanism by which several other statins have been reported to interact with clarithromycin.The mechanism may be an an effect on OATP1B1. Rosuvastatin is an OATP1B1 substrate. Monitor for clinical effectiveness of rosuvastatin and for potential myopathy.
Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with rosuvastatin. Taking these drugs together may significantly increase rosuvastatin plasma concentrations, potentially resulting in myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP); ledipasvir is a BCRP inhibitor.
Leflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Letermovir: (Moderate) Closely monitor for rosuvastatin-related adverse events (myopathy, rhabdomyolysis) and consider a rosuvastatin dose reduction if administered with letermovir. Do not exceed a rosuvastatin dose of 5 mg daily if the patient is also receiving cyclosporine. The magnitude of this interaction may be increased if letermovir is given with cyclosporine. Concurrent administration of letermovir, an organic anion-transporting polypeptide (OATP1B1/3) inhibitor, with rosuvastatin, an OATP1B1/3 substrate, may result in a clinically relevant increase in rosuvastatin plasma concentration.
Levonorgestrel; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Lopinavir; Ritonavir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with lopinavir; do not exceed a rosuvastatin dosage of 10 mg once daily. When rosuvastatin was coadministered with lopinavir in healthy volunteers, the Cmax and AUC of rosuvastatin was increased 5-fold and 2-fold, respectively. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); lopinavir is OATP1B1 inhibitor. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Lovastatin; Niacin: (Major) There is no clear indication for routine use of niacin in combination with rosuvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with rosuvastatin. If coadministered, consider lower starting and maintenance does of rosuvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue rosuvastatin immediately if myopathy is diagnosed or suspected.
Maralixibat: (Minor) Maralixibat may reduce the oral absorption of HMG-CoA reductase inhibitors, also known as statins, which may reduce their efficacy. This risk is greatest with maralixibat doses greater than 4.75 mg. Monitor statin therapy and adjust the dose as needed based on clinical response. Maralixibat is a OATP2B1 inhibitor and statins are OATP2B1 substrates.
Maribavir: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with maribavir. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and maribavir is a BCRP inhibitor.
Mestranol; Norethindrone: (Minor) Mestranol is converted to ethinyl estradiol. When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Midostaurin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with midostaurin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP and OATP1B1/3 substrate and midostaurin is a BCRP and OATP1B1 inhibitor.
Niacin, Niacinamide: (Major) There is no clear indication for routine use of niacin in combination with rosuvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with rosuvastatin. If coadministered, consider lower starting and maintenance does of rosuvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue rosuvastatin immediately if myopathy is diagnosed or suspected.
Niacin; Simvastatin: (Major) There is no clear indication for routine use of niacin in combination with rosuvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with rosuvastatin. If coadministered, consider lower starting and maintenance does of rosuvastatin. Monitor patients closely for myopathy or rhabdomyolysis, particularly in the early months of treatment or after upward dose titration of either drug. Consider monitoring serum creatinine phosphokinase (CPK) and potassium periodically in such situations. Discontinue rosuvastatin immediately if myopathy is diagnosed or suspected.
Nirmatrelvir; Ritonavir: (Major) Consider temporary discontinuation of rosuvastatin during treatment with ritonavir-boosted nirmatrelvir; if this is not feasible, consider an alternative COVID-19 therapy. Rosuvastatin does not need to be held prior to or after completing ritonavir-boosted nirmatrelvir. Coadministration may increase rosuvastatin exposure resulting in increased toxicity. Rosuvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Norethindrone; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Norgestimate; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Norgestrel: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.1 to 1.3-fold increase in the AUC and maximal concentrations of norgestrel. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of norgestrel, such as breast tenderness, nausea, headache, or fluid retention.
Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to rosuvastatin. Rosuvastatin is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
Ombitasvir; Paritaprevir; Ritonavir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen.
Omeprazole; Sodium Bicarbonate: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Oritavancin: (Moderate) Rosuvastatin is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated rosuvastatin plasma concentrations. If these drugs are administered concurrently, monitor patients for signs of rosuvastatin toxicity, such as muscle aches, muscle pain or tenderness, general weakness or fatigue, side or back pain, or decreased urination.
Osimertinib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including rhabdomyolysis and myopathy, if coadministration with osimertinib is necessary. Rosuvastatin is a BCRP substrate and osimertinib is a BCRP inhibitor. Concomitant use increased the AUC of rosuvastatin by 35% and the Cmax by 72%.
Oteseconazole: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with oteseconazole. Oteseconazole increased rosuvastatin exposure by 114%. Rosuvastatin is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Pacritinib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with pacritinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and pacritinib is a BCRP inhibitor.
Pirtobrutinib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with pirtobrutinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and pirtobrutinib is a BCRP inhibitor. Concomitant use was observed to increase rosuvastatin overall exposure by 140%.
Pretomanid: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with pretomanid. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and pretomanid is a BCRP inhibitor.
Probenecid; Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Red Yeast Rice: (Contraindicated) Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis.
Regorafenib: (Major) Do not exceed a rosuvastatin dose of 10 mg once daily when coadministered with regorafenib. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter breast cancer resistance protein (BCRP) and regorafenib is a BCRP inhibitor. Coadministration with regorafenib increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and 4.6-fold, respectively. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Rolapitant: (Moderate) Avoid the concurrent use of rosuvastatin and rolapitant if possible; if coadministration is necessary, use the lowest effective dose of rosuvastatin and monitor for rosuvastatin-related adverse effects. Rosuvastatin is a substrate of the Breast Cancer Resistance Protein (BCRP), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as rosuvastatin. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
Saquinavir: (Major) The concurrent use of saquinavir boosted with ritonavir and rosuvastatin should be avoided if possible due to the potential for myopathies, including rhabdomyolysis. Coadministration of saquinavir boosted with ritonavir and rosuvastatin results in an increased plasma concentration of rosuvastatin.The combination saquinavir/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. If coadministered, use the lowest possible dose of rosuvastatin with careful clinical monitoring,
Segesterone Acetate; Ethinyl Estradiol: (Minor) When coadministered with oral contraceptives during drug interaction studies, rosuvastatin produced an approximately 1.3-fold increase in the AUC and maximal concentrations of ethinyl estradiol. The changes are not likely to be of clinical consequence for most patients; some patients may experience increases in common side effects of hormonal contraceptives, such as breast tenderness, nausea, headache, or fluid retention.
Simeprevir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with simeprevir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1 and OATP1B3) and breast cancer resistance protein (BCRP) and simeprevir is an inhibitor of these transporters. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Sodium Bicarbonate: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
Sodium Phenylbutyrate: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with sodium phenylbutyrate. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and sodium phenylbutyrate is a BCRP inhibitor.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with sodium phenylbutyrate. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and sodium phenylbutyrate is a BCRP inhibitor. (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with taurursodiol. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and taurursodiol is a BCRP inhibitor.
Sofosbuvir; Velpatasvir: (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with velpatasvir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP) and OATP1B1 transporters, while velpatasvir inhibits both BCRP and OATP1B1.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with rosuvastatin. Taking these drugs may significantly increase systemic exposure to rosuvastatin, which may increase the risk of myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptides (OATP1B1/1B3) transporters, while voxilaprevir inhibits both BCRP and OATP1B1/1B3. (Major) Initiate rosuvastatin at a reduced dosage of 5 mg once daily if coadministered with velpatasvir; do not exceed a rosuvastatin dosage of 10 mg once daily. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP) and OATP1B1 transporters, while velpatasvir inhibits both BCRP and OATP1B1.
Sotorasib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with sotorasib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and sotorasib is a BCRP inhibitor.
Sparsentan: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with sparsentan. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and sparsentan is a BCRP inhibitor.
Tacrolimus: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and rosuvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of rosuvastatin of 5 mg/day is recommended.
Tafamidis: (Major) Avoid concomitant use of rosuvastatin and tafamidis. Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. If concomitant use is necessary, initiate rosuvastatin at 5 mg once daily and do not exceed a rosuvastatin dose of 10 mg once daily; monitor for adverse effects. Rosuvastatin is a BCRP substrate and tafamidis is a BCRP inhibitor. Coadministration with tafamidis increased rosuvastatin exposure by almost 2-fold.
Tedizolid: (Moderate) If possible, stop use of rosuvastatin temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for rosuvastatin-associated adverse events. In clinical trials involving healthy adults, multiple doses of oral tedizolid (200 mg PO once daily) increased the Cmax and AUC of rosuvastatin (10 mg single PO dose) by approximately 55% and 70%, respectively. Rosuvastatin is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
Telbivudine: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
Teriflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Tipranavir: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when tipranavir is given in combination with most HMG-CoA reductase inhibitors. If rosuvastatin is to be used concomitantly with tipranavir (in the FDA approved dosage regimen), use the lowest possible dose with careful monitoring, or consider an alternative HMG-CoA reductase inhibitor that is less significantly metabolized by CYP3A4 (i.e., fluvastatin, pravastatin).
Voclosporin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with voclosporin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and voclosporin is an OATP1B1/3 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) The lowest dose of rosuvastatin should be considered if coadministered with clarithromycin. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and rosuvastatin. Rosuvastatin is not extensively metabolized by CYP3A4, a mechanism by which several other statins have been reported to interact with clarithromycin.The mechanism may be an an effect on OATP1B1. Rosuvastatin is an OATP1B1 substrate. Monitor for clinical effectiveness of rosuvastatin and for potential myopathy.
Warfarin: (Moderate) Addition of rosuvastatin to warfarin therapy has resulted in significant increases in the INR (> 4, baseline 2 to 3), without a change in warfarin plasma concentrations. INR should be monitored at baseline prior to rosuvastatin initiation, and frequently following initiation of rosuvastatin therapy and subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Rosuvastatin has not been associated with bleeding or with changes in INR in patients not taking oral anticoagulants.
Rosuvastatin is a selective, competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol levels in hepatic cells. This, in turn, results in upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation. Due to its unique structural binding sites and relative hydrophilicity, rosuvastatin has a high affinity for HMG-CoA reductase and is selective for hepatic cells with minimal uptake by nonhepatic tissues. In a rat hepatocyte model, rosuvastatin was found to be 7-fold more potent than atorvastatin; in a model using human HMG-CoA reductase, rosuvastatin was 8-fold more potent than pravastatin. Rosuvastatin decreases total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B while increasing HDL. During a Phase II study, rosuvastatin doses of 1 to 80 mg lowered LDL cholesterol by 34 to 65%. Evening or morning administration does not affect rosuvastatin pharmacokinetics or antilipemic effects.
HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.
Rosuvastatin is administered orally. Unlike prodrugs, such as lovastatin or simvastatin, the majority of HMG-CoA reductase inhibitory activity (90%) in plasma is associated with the parent compound. Evening or morning dosing does not affect pharmacokinetic parameters or cholesterol-lowering effects. Rosuvastatin is about 88% bound to plasma proteins. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by rosuvastatin. Studies with human hepatic CYP450 microsomes and human hepatocytes have suggested little or no metabolism of rosuvastatin via the CYP3A4 isoenzyme; hepatic metabolism of the drug via CYP450 is limited. Rosuvastatin appears to be metabolized to a limited extent to an N-desmethyl metabolite (7-fold less potent than rosuvastatin) and a 5S-lactone product. In human hepatocytes, the in vitro formation of the N-desmethyl metabolite is inhibited by sulphaphenazole, and to a lower extent by omeprazole, which suggests some metabolism by CYP2C9 and CYP2C19 isoenzymes. Rosuvastatin is eliminated primarily unchanged via the fecal route (90%, including unabsorbed drug), and approximately 10% of the dose is eliminated renally. Approximately 72% of an absorbed dose is excreted via the bile and about 28% is excreted renally. Rosuvastatin has a plasma half-life of about 19 to 20 hours.
Affected cytochrome P450 isoenzymes and drug transporters: OATP1B1, BCRP
Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of medications that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations. CYP3A4 is not involved in rosuvastatin metabolism to a clinically relevant extent. Since hepatic metabolism is a minor pathway for elimination, clinically significant drug interactions with rosuvastatin via CYP450 are limited. In vivo studies have demonstrated that azole antifungals (e.g., itraconazole, ketoconazole, fluconazole) and erythromycin have minimal or no effects on the pharmacokinetics of rosuvastatin.
-Route-Specific Pharmacokinetics
Oral Route
The bioavailability of rosuvastatin is approximately 20%, with peak rosuvastatin plasma concentrations reached within 3 to 5 hours after oral dosing. Food reduces absorption rate by 20%, but does not affect overall bioavailability.
-Special Populations
Hepatic Impairment
In patients with chronic alcohol hepatic disease, the AUC of rosuvastatin is increased by 5 to 21% in patients with Child-Pugh class A and B disease, respectively.
Renal Impairment
Rosuvastatin serum concentrations are increased approximately 3-fold in patients with severe renal impairment (CrCl less than 30 mL/min) vs. patients with normal renal function. Mild to moderate renal impairment did not impact rosuvastatin plasma concentrations. According to the manufacturer, hemodialysis does not significantly enhance the clearance of rosuvastatin. Rosuvastatin serum concentrations are increased approximately 50% in hemodialysis vs. patients with normal renal function.
Pediatrics
In a population pharmacokinetic analysis of 2 pediatric trials involving patients 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients.
Geriatric
Minimal differences in rosuvastatin pharmacokinetics have been noted for elderly vs. younger adult volunteers (AUC increased by 6%); these differences are not considered to be clinically significant.
Gender Differences
Minimal differences in rosuvastatin pharmacokinetics have been noted for male vs. female subjects (AUC decreased by 9%); these differences are not considered to be clinically significant.
Ethnic Differences
A population pharmacokinetic analysis revealed no clinically relevant differences in rosuvastatin pharmacokinetics among White, Hispanic, and Black or Afro-Caribbean patients. However, pharmacokinetic studies show an approximate 2-fold elevation in median exposure (AUC) in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore when compared with White patients residing in North America and Europe. No studies directly examining Asian ethnic populations residing in the US are available; therefore the contribution of environmental and genetic factors to the observed increases in rosuvastatin serum concentrations have not been determined.
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