Rosuvastatin; ezetimibe is an oral antilipemic combination. Rosuvastatin is an HMG-CoA reductase inhibitor (statin). Ezetimibe is a potent cholesterol absorption inhibitor and selectively blocks the intestinal absorption of cholesterol and related phytosterols. This combination medication is indicated as an adjunct to diet for the treatment of primary non-familial hyperlipidemia or as an adjunct to other lipid-lowering therapies for the treatment of homozygous familial hypercholesterolemia (HoFH) in adult patients. In clinical trials, rosuvastatin; ezetimibe therapy resulted in greater LDL-C reductions (56.5 to 59.5%) compared to rosuvastatin monotherapy (44.4 to 51.1%). Greater reductions in non-HDL-C, Apo-B, triglycerides, and total cholesterol were also seen with rosuvastatin; ezetimibe compared to ezetimibe. There was no significant differences in adverse events between rosuvastatin; ezetimibe and rosuvastatin therapies. The most commonly reported adverse reactions with rosuvastatin; ezetimibe therapy were gastrointestinal (2.4 to 3%) and musculoskeletal (2 to 2.4%) compared to 0.5 to 4.1% and 0.5 to 0.8% with rosuvastatin, respectively.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Swallow tablets whole with or without food. Do not crush, dissolve, or chew tablets.
-May be taken at any time of the day.
-Instruct patients not to take 2 doses of rosuvastatin; ezetimibe within 12 hours of each other.
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 cases 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.
Rhabdomyolysis and myopathy (muscle pain, tenderness, or weakness with elevated creatine kinase) with acute renal failure due to myoglobinuria have been reported with statins, including rosuvastatin. Rhabdomyolysis may occur anytime during drug treatment and the risk may be increased by a number of confounding factors including age, concomitant drug therapy, renal dysfunction, race, and concomitant disease states. The risk of rhabdomyolysis and myopathy can occur at any dose level but increases in a dose-dependent manner with rosuvastatin 40 mg; ezetimibe 10 mg daily having the highest risk. Risk of myopathy is higher in Asian patients receiving statin therapy. Myalgia and elevations in creatinine phosphokinase (CPK) occurred in 2.8 to 12.7% and 2.6%, respectively, of rosuvastatin patients compared to 1.3 to 12.1% and 0.7%, respectively, of placebo patients in clinical trials. In clinical studies, myalgia and musculoskeletal pain in the extremity were reported in 3.2% and 2.1%, respectively, of patients receiving ezetimibe plus a statin compared to 2.7% and 1.9%, respectively, of patients receiving a statin. Musculoskeletal pain in the extremity was reported in 2.7% of ezetimibe patients and 2.5% of placebo patients. In clinical studies, dipstick-positive proteinuria and microscopic hematuria were reported in rosuvastatin patients; incidence was higher with 40 mg/day compared to lower rosuvastatin dosages. In patients who have unexplained persistent proteinuria or hematuria during routine urinalysis testing, consider a reduction in rosuvastatin; ezetimibe dosage. Patients receiving rosuvastatin; ezetimibe therapy should be monitored for symptoms of myopathy or rhabdomyolysis (myalgia, lethargy/drowsiness, fatigue, weakness, fever, and/or myasthenia) and CPK serum concentrations. Muscle symptoms and CPK elevations may resolve upon rosuvastatin; ezetimibe discontinuation.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) 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 myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. 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.
Although rare, severe hepatotoxicity may occur during HMG-CoA reductase inhibitor therapy. Fatal and non-fatal hepatic failure, hepatitis, and jaundice have been reported with postmarketing use of rosuvastatin. Hepatitis has also been reported with postmarketing use of ezetimibe. Pancreatitis was reported during clinical trials with rosuvastatin and postmarketing use of ezetimibe. Elevated hepatic enzymes have also occurred with rosuvastatin therapy. In clinical studies, elevations in hepatic enzymes to more than 3 times the upper limit of normal (ULN) occurred in 1.1% of rosuvastatin patients compared to 0.5% of placebo patients; the incidence was 2.6% with rosuvastatin 40 mg/day. Most of the cases of elevated hepatic enzymes have developed soon after initiation of therapy, were not associated with symptoms, were transient and resolved with continued therapy or improved following a brief interruption in therapy. In clinical studies, elevations in hepatic enzymes to more than 3 times the ULN occurred in 0.5% of ezetimibe patients compared to 0.3% of placebo patients. In studies involving ezetimibe and statins, elevations in hepatic enzymes to more than 3 times the ULN occurred in 1.3% of ezetimibe plus statin patients compared to 0.4% of statin patients. Cholelithiasis and cholecystitis have been reported with postmarketing use of ezetimibe. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly interrupt therapy.
Adverse gastrointestinal effects reported during clinical trials of rosuvastatin compared to placebo include nausea (3.4% vs. 3.1%) and constipation (2.4% vs. 2.4%). Abdominal pain was also reported with rosuvastatin therapy. Diarrhea was reported in 2.5% if ezetimibe patients compared to 2.2% of placebo patients in clinical trials. Abdominal pain and nausea have been reported with postmarketing use of ezetimibe.
In rosuvastatin clinical trials, headache, asthenia, and dizziness were reported in 5.5 to 6.4%, 2.7%, and 4% of rosuvastatin patients, respectively, compared to 5 to 5.3%, 2.6%, and 2.8% of placebo patients, respectively. Fatigue was reported in 2.4% and 2% of ezetimibe and ezetimibe plus statin patients, respectively, compared to 1.5 to 1.6% of placebo patients in clinical studies. There have been rare postmarketing reports of impaired cognition (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with all statins. These reports of impaired cognition have generally not been serious and have been reversible upon statin discontinuation. Time to onset of cognitive impairment symptoms ranged from 1 day to years after initiation of therapy and the median time to symptom resolution is 3 weeks. Depression, insomnia, and nightmares have been reported with postmarketing use of rosuvastatin. Dizziness, depression, paresthesias, and headache have been reported with postmarketing use of ezetimibe.
Arthralgia has been reported during therapy with rosuvastatin and ezetimibe. In clinical trials, arthralgia was reported in 10.1% of rosuvastatin patients compared to 7.1% of placebo patients. In ezetimibe clinical studies, arthralgia was reported in 3% of ezetimibe patients and 2.2% of placebo patients. Arthralgia and back pain were reported in 2.6% and 2.4% of ezetimibe plus statin patients, respectively, compared to 2.4% and 2.3% of statin patients, respectively.
An association between HMG-CoA reductase inhibitors, 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 when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy often 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.
Elevated glycated hemoglobin, hyperglycemia, and new cases of diabetes mellitus have been reported in patients taking rosuvastatin. In a double-blind, placebo-controlled study, the incidence of diabetes mellitus was higher with rosuvastatin at 2.8% compared to placebo at 2.3%. Additionally, the number of patients with a hemoglobin A1C greater than 6.5% was significantly higher with rosuvastatin compared to placebo. 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.49064 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 during clinical trials. During postmarketing experience with ezetimibe, hypersensitivity reactions (including anaphylactoid reactions, angioedema, rash, and urticaria) and erythema multiforme have been reported.
In clinical trials evaluating ezetimibe monotherapy, upper respiratory tract infection (4.3% with ezetimibe vs. 2.5% with placebo), sinusitis (2.8% vs. 2.2%) and influenza (2% vs. 1.5%) were reported. During ezetimibe plus statin trials, naso-pharyngitis, upper respiratory tract infection, and influenza were reported in 3.7%, 2.9%, and 2.2% of patients receiving combination therapy, respectively, compared to 3.3%, 2.8%, and 2.1% of statin patients, respectively.
Thrombocytopenia has been reported with postmarketing use of both rosuvastatin and ezetimibe.
Interstitial lung disease has been reported with postmarketing use of rosuvastatin.
HMG-CoA reductase inhibitors, 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.
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.
Rosuvastatin; ezetimibe is contraindicated in patients with active hepatic disease/failure and hepatic decompensation (decompensated cirrhosis). In addition, patients should minimize alcohol intake while receiving rosuvastatin; ezetimibe therapy, the risk of acute liver injury is increased in alcoholism. Patients with a history of hepatic disease may be at an increased risk for hepatic injury. Following administration of a single 10 mg ezetimibe dose in patients with mild hepatic impairment (Child-Pugh A), the mean AUC for total ezetimibe increased by 1.7-fold compared to healthy subjects. In patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, the mean AUC values for ezetimibe (unconjugated and conjugated) increased by about 3 to 4-fold and 5 to 6-fold, respectively, compared to healthy patients. Compared to patients without hepatic impairment, the mean AUC for total ezetimibe increased by approximately 4-fold following administration of ezetimibe 10 mg PO once daily for 14 days in patients with moderate hepatic impairment. Consider assessing liver enzymes prior to initiation of rosuvastatin; ezetimibe therapy and repeat as clinically indicated. 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. Instruct patients to promptly report any symptoms of hepatic injury (e.g. fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice). If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin; ezetimibe, therapy should be interrupted. If an alternate etiology is not found, do not restart rosuvastatin; ezetimibe.
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level but increase in a dose-dependent manner with rosuvastatine 40 mg; ezetimibe 10 mg daily having the highest risk. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase (CPK). Rosuvastatin should be discontinued immediately in any patient who develops myopathy, elevations in CPK, or evidence of drug-induced rhabdomyolysis or a decrease in renal function. Predisposing risk factors for myopathy include advanced age (65 years or more), renal disease or renal insufficiency, females, hypotension, acute infection, endocrine disease (including uncontrolled hypothyroidism), electrolyte imbalance, uncontrolled seizure disorder, major surgery, and trauma. The risk of developing myopathy is also increased when HMG-CoA reductase inhibitors are used in combination with certain drugs. Rosuvastatin; ezetimibe may need to be temporarily withheld during acute medical conditions or interacting agents may need to be temporarily stopped to help mitigate risks. 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, consider a reduction in rosuvastatin; ezetimibe dosage. 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.
Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) 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 myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. 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.
Use caution in prescribing rosuvastatin; ezetimibe to Asian patients. Pharmacokinetic studies show an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects compared with White patients. Asian patients may be at an increased risk of developing myopathy while on rosuvastatin; ezetimibe therapy. Initiate therapy at the lower dose of rosuvastatin 5 mg/ezetimibe 10 mg once daily. Consider the risks and benefits of treating Asian patients not adequately controlled at doses up to rosuvastatin 20 mg/ezetimibe 10 mg once daily.
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. 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. Counsel patients on the importance of optimizing lifestyle measures, including regular exercise, maintaining a healthy diet, and maintaining a healthy weight.
Since advanced age (65 years or more) is a predisposing risk factor for myopathy and rhabdomyolysis, rosuvastatin; ezetimibe should be prescribed with caution in the geriatric adult. Use cautious dose selection for older adults 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. In general, some geriatric patients may have an increased response to HMG-CoA reductase inhibitors; individualize dosage to clinical goals.
Rosuvastatin; ezetimibe should be discontinued once pregnancy is detected because of the potential effects of HMG-CoA reductase inhibitors on cholesterol pathways and the potential for fetal harm. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. In a cohort linkage study, no significant teratogenic effect from maternal use of statin therapy during the first trimester of pregnancy was found after adjusting for confounders. The relative risk of congential malformations was 1.07 (95% CI 0.85 to 1.37) between statin exposure versus non-statin exposure during the first trimester, after controlling for confounders. Majority of the patients started statin therapy prior to pregnancy and discontinued therapy during the first trimester of pregnancy. In rat studies, delayed ossification and decreased pup survival occurred at 10 times and 12 times, respectively, the rosuvastatin maximum recommended human dose (MRHD). Decreased fetal viability and maternal mortality was observed in pregnant rabbits that received 3 mg/kg rosuvastatin, which is dose equivalent to the MRHD of 40 mg/day. Rosuvastatin has been shown to cross the placenta in studies involving pregnant rats and rabbits. Ezetimibe was not teratogenic when orally administered to pregnant rats and rabbits at doses that were 10 to 150 times the MRHD. An increase in the incidence of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) was observed in pregnant rats that received 10 times the MRHD of ezetimibe. In pregnant rabbits at doses 150 times MRHD, an increased incidence of extrathoracic ribs was reported. Placental transfer studies found the fetal-maternal plasma exposure ratio for total ezetimibe (conjugated and unconjugated ezetimibe) to be 1.5 for rats and 0.03 for rabbits on gestation day 20 and 22, respectively. When ezetimibe and a statin were coadministered to rats and rabbits during organogenesis, reproductive findings were found to occur at lower doses with combination therapy compared to either agent administered alone.
Limited data indicate that rosuvastatin is excreted into human breast milk. In a single case report of lactating woman taking rosuvastatin 40 mg PO daily, the rosuvastatin breast milk concentration ranged from 21.9 to 22.8 ng/mL over 3 days at 3, 3.8, or 21 hours after administration; rosuvastatin serum concentration 23 hours after intake was 18 ng/mL. There is no information on the presence of ezetimibe in human milk. There is no available information on the effects of rosuvastatin; ezetimibe on the breastfed infant or the effects of the combination on milk production. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway; other adverse effects to a nursing infant are possible. Due to the potential risk to the infant, breast-feeding is not recommended during rosuvastatin; ezetimibe therapy. If pharmacotherapy is necessary for the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Use rosuvastatin; ezetimibe with caution in persons with myasthenia gravis. Closely monitor for myasthenia gravis exacerbation and encourage reporting of any muscle-related symptoms. Exacerbation of myasthenia gravis, including ocular myasthenia gravis, has been reported during treatment with statins, including rosuvastatin. Reports of recurrence have been noted when the same or a different statin was administered. The onset of symptom exacerbation following initiation of statin therapy has ranged from 1 week to 4 months. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents.
For the treatment of primary nonfamilial hypercholesterolemia (including hyperlipidemia and hyperlipoproteinemia) as an adjunct to diet to reduce LDL-C and homozygous familial hypercholesterolemia alone or as adjunct to other LDL-C lowering therapies to reduce LDL-C:
Oral dosage:
Adults: 5 mg rosuvastatin/10 mg ezetimibe to 40 mg rosuvastatin/10 mg ezetimibe PO once daily. Dose depends on indication, LDL-C, and individual risk for cardiovascular events. Base dose on an equivalent dose of rosuvastatin and 10 mg ezetimibe for persons switching from coadministration of a statin and ezetimibe. Monitor lipid concentrations after starting therapy or adjusting dose within 2 or more weeks and adjust dose if needed. Max: 40 mg/day rosuvastatin/10 mg/day ezetimibe. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Asian Adults: 5 mg rosuvastatin/10 mg ezetimibe PO once daily, initially. Monitor lipid concentrations after starting therapy or adjusting dose within 2 or more weeks and adjust dose if needed. Max: 20 mg/day rosuvastatin/10 mg/day ezetimibe. Consider the risk/benefit when treating Asian persons not adequately controlled at doses up to 20 mg/day rosuvastatin/10 mg/day ezetimibe. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
40 mg/day PO rosuvastatin and 10 mg/day PO ezetimibe.
-Geriatric
40 mg/day PO rosuvastatin and 10 mg/day PO ezetimibe.
-Adolescents
Safety and efficacy have not been established.
-Children
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
Rosuvastatin; ezetimibe is contraindicated in patients with acute liver injury or decompensated cirrhosis.
Patients with Renal Impairment Dosing
CrCl 30 mL/min or greater: No dosage adjustment needed.
CrCl less than 30 mL/min: Reduce initial dose to rosuvastatin 5 mg/ezetimibe 10 mg PO once daily for patients not receiving hemodialysis. Maximum dose is rosuvastatin 10 mg/ezetimibe 10 mg PO once daily.
*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.
Aluminum Hydroxide: (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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Carbonate: (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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Hydroxide: (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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aluminum Hydroxide; Magnesium Trisilicate: (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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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.
Asciminib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with asciminib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP and OATP1B1/3 substrate and asciminib is a BCRP and OATP1B1/3 inhibitor.
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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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.
Belumosudil: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with belumosudil. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and belumosudil is a BCRP inhibitor.
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. (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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. (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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. (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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. (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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. (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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. (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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.
Cholestyramine: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants, such as cholestyramine. The incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively.
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: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
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.
Clopidogrel: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clopidogrel. Concurrent use has been observed to increase rosuvastatin overall exposure by 1.4-fold and 2-fold in patients receiving 75 mg and 300 mg of clopidogrel, respectively.
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: (Moderate) Concomitant use of colchicine and HMG-CoA reductase inhibitors (statins) may increase the risk for myopathy and rhabdomyolysis. If concomitant use is necessary, monitor for signs and symptoms of muscle pain, tenderness, or weakness especially following therapy initiation and upward dose titration. The use of low dose colchicine may further reduce the risk for myopathy.
Colesevelam: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colesevelam with ezetimibe; however, this potential interaction has not been studied.
Colestipol: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colestipol with ezetimibe; however, this potential interaction has not been studied.
Cyclosporine: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and 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.
Danicopan: (Major) Limit the dose of rosuvastatin to 10 mg once daily and monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with danicopan. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and danicopan is a BCRP inhibitor. Coadministration with danicopan increased the overall exposure of rosuvastatin by approximately 2-fold.
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.
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 an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with elexacaftor. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and elexacaftor is an OATP1B1/3 inhibitor.
Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and ezetimibe are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as ezetimibe, may exhibit an increase in systemic exposure if coadministered with 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) Do not exceed a rosuvastatin dose of 10 mg once daily if concomitant use of enasidenib is necessary. Concomitant use may increase rosuvastatin exposure and the risk for rosuvastatin-related adverse reactions, such as myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the drug transporters OATP1B1/3 and BCRP and enasidenib is an OATP1B1/3 and BCRP inhibitor. Coadministration of enasidenib increased rosuvastatin exposure by more than 2.4-fold.
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; 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. (Moderate) Monitor for cholelithiasis symptoms during concomitant ezetimibe and fenofibrate use. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. If cholelithiasis is suspected, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.
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. (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
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. (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
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: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
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.
Leniolisib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with leniolisib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of BCRP and OATP1B1/3; leniolisib is an inhibitor of BCRP and OATP1B1/3.
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.
Levonorgestrel; 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.
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.
Magnesium Hydroxide: (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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Magnesium Salts: (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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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.
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.
Momelotinib: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with momelotinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and momelotinib is a BCRP 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.
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.
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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
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: (Moderate) Concomitant use of colchicine and HMG-CoA reductase inhibitors (statins) may increase the risk for myopathy and rhabdomyolysis. If concomitant use is necessary, monitor for signs and symptoms of muscle pain, tenderness, or weakness especially following therapy initiation and upward dose titration. The use of low dose colchicine may further reduce the risk for myopathy.
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.
Resmetirom: (Major) Limit the dose of rosuvastatin to 20 mg once daily during concomitant use with resmetirom. Concomitant use was observed to increase rosuvastatin overall exposure by 1.8-fold which may increase the risk for rosuvastatin-related adverse effects.
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.
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. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Sodium Phenylbutyrate; Taurursodiol: (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.
Sulfacetamide; Sulfur: (Moderate) HMG-CoA reductase inhibitors have been administered safely with niacin (nicotinic acid) in some patients; however the risk of potential myopathy should be considered. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in lipid-altering doses (i.e., >=1 g/day) and HMG-CoA reductase inhibitors (Statins) concurrently. The serious risk of myopathy or rhabdomyolysis should be carefully weighed against the potential risks. Patients undergoing combined therapy should be carefully monitored for myopathy or rhabdomyolysis, particularly in the early months of treatment or during periods of upward dose titration of either drug. Chinese patients receiving concomitant lipid-altering doses of niacin-containing products should not receive the 80 mg dose of simvastatin due to increased risk of myopathy.
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 20 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.
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).
Trofinetide: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with trofinetide. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and trofinetide is an OATP1B1/3 inhibitor.
Vitamin B Complex Supplements: (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.
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: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
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. (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored.
Rosuvastatin and ezetimibe exhibit complementary mechanisms that reduce LDL-C, total cholesterol, non-high density lipoprotein cholesterol (non-HDL-C), and apolipoprotein-B (Apo-B). In clinical trials, rosuvastatin; ezetimibe therapy resulted in greater LDL-C reductions (56.5 to 59.5%) compared to rosuvastatin monotherapy (44.4 to 51.1%). Greater reductions in non-HDL-C, Apo-B, and total cholesterol were also seen with rosuvastatin; ezetimibe compared to ezetimibe.
-Rosuvastatin: Rosuvastatin is an 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-C from the circulation. Rosuvastatin also inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles. Rosuvastatin decreases total cholesterol, LDL-C, triglycerides, and Apo-B while increasing HDL-C. During a Phase II study, rosuvastatin doses of 1 to 80 mg lowered LDL-C by 34 to 65%.
-Ezetimibe: Ezetimibe lowers serum cholesterol concentrations by selectively inhibiting the absorption of cholesterol and related phytosterols by the small intestine. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid secretion. Ezetimibe localizes at the brush border of the small intestine. The molecular target of ezetimibe has been show to the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the blood clearance of cholesterol. When ezetimibe is given as monotherapy, a compensatory increase in cholesterol synthesis occurs. With ongoing therapy, the overall effects of ezetimibe monotherapy are to reduce total cholesterol (13%), LDL-cholesterol (18%), and Apo-B (16%) in patients with hypercholesterolemia. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols (sitosterol and campesterol). In a 2-week study of 18 hypercholesterolemic patients, ezetimibe has been reported to inhibit intestinal cholesterol absorption by 54% relative to placebo.
Rosuvastatin; ezetimibe is administered orally. No clinically significant pharmacokinetic interactions have been noted when ezetimibe was coadministered with rosuvastatin.
-Rosuvastatin: Rosuvastatin does not undergo extensive metabolism, with approximately 10% of a radiolabeled doses recovered as a metabolite. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is associated with the parent compound. Rosuvastatin appears to be metabolized to a limited extent to an N-desmethyl metabolite (approximately one-sixth to one-half the potency of rosuvastatin) and a 5S-lactone product. Following oral administration, 90% of rosuvastatin and its metabolites are excreted in the feces. Following intravenous administration, approximately 72% of the total body clearance was via the hepatic route and 28% via the renal route. Rosuvastatin is 88% bound to plasma proteins, primarily albumin, and has a mean Vd of 134 L. The protein binding is reversible and independent of plasma concentrations. Rosuvastatin has a plasma half-life of about 19 to 20 hours.
-Ezetimibe: Ezetimibe is administered orally. Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human plasma proteins. Ezetimibe is rapidly metabolized by glucuronidation to ezetimibe-glucuronide in the small intestine and liver. Metabolism by oxidative metabolism is minimal. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10% to 20% and 80% to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. After oral administration of radiolabeled ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) accounts for approximately 93% of the total plasma radioactivity. After 48 hours, the plasma radioactivity is undetectable. Over a 10-day period, approximately 78% and 11% of the administered dose is recovered in the feces and urine, respectively. Ezetimibe is the major component recovered in the feces and accounts for 69% of the administered dose, while ezetimibe-glucuronide is the major component recovered in the urine and accounts for 9% of the administered dose.
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. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P450 isoenzymes and transporters.
-Route-Specific Pharmacokinetics
Oral Route
-Rosuvastatin: The bioavailability of rosuvastatin is approximately 20%, with peak rosuvastatin plasma concentrations reached within 3 to 5 hours after oral dosing. Food reduces absorption by 20%, but does not affect overall bioavailability.
-Ezetimibe: Following oral administration of a single 10 mg dose to fasted adults, the mean Cmax was 3.4 to 5.5ng/mL and time to maximum concentration was 4 to 12 hours for ezetimibe. For ezetimibe-glucuronide, the mean Cmax was 45 to 71 ng/mL and time to maximum concentration was 1 to 2 hours. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases the Cmax of ezetimibe by 38%.
-Special Populations
Hepatic Impairment
-Rosuvastatin: In patients with chronic alcohol liver disease, the AUC of rosuvastatin is increased by 5% and 21% in patients with Child-Pugh class A and B disease, respectively, and the Cmax by 60% and 100%, respectively.
-Ezetimibe: Although pharmacokinetic differences have been identified in patients with mild hepatic impairment (Child-Pugh A), no dosage adjustments for ezetimibe are indicated. Significant increases in ezetimibe exposure occur in patients with moderate to severe impairment (Child-Pugh B or C); ezetimibe is not recommended for use in these patients. Following administration with a single 10 mg ezetimibe dose in patients with mild hepatic impairment (Child-Pugh A), the mean AUC for total ezetimibe increased by 1.7-fold compared to healthy subjects. In patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, the mean AUC values for total ezetimibe (unconjugated and conjugated) and ezetimibe increased 3 to 4-fold and 5 to 6-fold, respectively, compared to healthy patients. Compared to patients without hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased by approximately 4-fold following administration of ezetimibe 10 mg PO once daily for 14 days in patients with moderate hepatic impairment.
Renal Impairment
-Rosuvastatin: 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.
-Ezetimibe: Although pharmacokinetic differences have been identified in severe renal impairment, no dosage adjustments for ezetimibe are indicated. In 8 patients with severe renal impairment (mean CrCl 30 mL/min/1.73m2 or lower), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe are increased by approximately 1.5-fold, compared to healthy subjects (n=9).
Geriatric
-Rosuvastatin: Minimal differences in rosuvastatin pharmacokinetics have been noted for elderly versus younger adult volunteers (AUC increased by 6%); these differences are not considered to be clinically significant.
-Ezetimibe: With repeated dosing of 10 mg daily for 10 days, plasma concentrations for total ezetimibe are about 2-fold higher in elderly subjects compared to younger adults; however, no dosage adjustment is recommended in elderly patients.
Gender Differences
-Rosuvastatin: 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.
-Ezetimibe: Although pharmacokinetic differences have been identified in women, no dosage adjustments for ezetimibe are indicated. In a multiple-dose study of 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (greater than 20%) for women relative to men.
Ethnic Differences
-Rosuvastatin: 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 and Cmax) in Asian subjects compared to White patients.
-Ezetimibe: Race was not shown to have an effect on the pharmacokinetics of ezetimibe.