Ezetimibe; simvastatin (Vytorin) is an oral antilipemic combination. Ezetimibe is a potent cholesterol absorption inhibitor and selectively blocks the intestinal absorption of cholesterol and related phytosterols. Simvastatin is an HMG-CoA reductase inhibitor ('statin'). The combination of ezetimibe with a statin results in synergistic cholesterol-lowering effects. Vytorin (ezetimibe 10 mg combined with simvastatin 10 to 80 mg) reduces LDL-cholesterol by approximately 45-60% compared to LDL reduction ranges of 33-49% achieved by simvastatin monotherapy (10-80 mg/day) and 36-53% attained by atorvastatin (10-80 mg/day), respectively, during comparative clinical trials. The Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial compared intensive lipid lowering with ezetimibe 10 mg/day PO and simvastatin 40 mg/day PO to placebo in patients with mild-to-moderate, asymptomatic aortic stenosis and no traditional indication for lipid lowering therapy at baseline. Although there was a statistically significant reduction in ischemic cardiovascular events, mainly due to fewer patients requiring coronary-artery bypass grafting (CABG) (HR, 0.78; 95% CI, 0.63-0.97; p = 0.02), treatment with ezetimibe; simvastatin did not significantly reduce the risk of the primary endpoint, which was a composite endpoint of major cardiovascular events from multiple causes (HR, 0.96; 95% CI, 0.83-1.12; p = 0.59). Additionally, the results of The Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial showed no significant difference between ezetimibe plus simvastatin and simvastatin alone in progression of atherosclerotic plaque in the inner walls of the carotid arteries despite greater lowering of LDL-cholesterol with ezetimibe plus simvastatin compared to simvastatin alone. However, after reviewing the ENHANCE clinical study report, the FDA released a statement that their position remained that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease. Based on current available data, FDA recommends that patients should not stop taking ezetimibe; simvastatin or other cholesterol lowering medications. Based on results from the Study of Heart and Renal Protection (SHARP), an FDA advisory panel voted unanimously in November 2011 to recommend approval of ezetimibe; simvastatin for the prevention of myocardial infarction and stroke in patients with pre-dialysis chronic kidney disease (CKD). However, in January 2012 the FDA announced the indication was not approved because the SHARP study was not designed to assess the independent contributions of ezetimibe and simvastatin to the observed effect. SHARP randomized 9270 patients with CKD and no known myocardial infarction or coronary revascularization to either ezetimibe; simvastatin 10/20 mg/day PO or placebo. Treatment with ezetimibe; simvastatin resulted in a 17% relative risk reduction in major atherosclerotic events compared to placebo (11.3% vs. 13.4%, respectively; RR 0.83, 95% CI 0.74-0.94; log-rank p = 0.0021). The trial was not sufficiently powered to examine the effects on major atherosclerotic events separately in dialysis and non-dialysis patients; therefore, the FDA advisory panel determined that there is insufficient evidence to recommend approval of ezetimibe; simvastatin for CKD patients receiving dialysis. In July 2004, ezetimibe; simvastatin (Vytorin) received its initial FDA approval for adjunctive therapy to diet in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia or mixed hyperlipidemia; the drug is also approved for patients with homozygous familial hypercholesterolemia (HoFH).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer ezetimibe; simvastatin as a single daily dose in the evening, with or without food.
-Dosing should occur either >= 2 hours before or >= 4 hours after administration of an interacting bile acid sequestrant.
This monograph discusses the use of the ezetimibe and simvastatin together. Consult individual drug monographs for more detailed information.
Preliminary results from the SEAS trial reported a potential association between the use of ezetimibe; simvastatin and increased diagnosis/death-rate for all types of cancer compared to placebo. However, cancer occurrence data from the SHARP and IMPROVE-IT trials combined indicate no overall excess of cancer (313 vs. 326 control; risk ratio, 0.96; 95% CI 0.82-1.12; p = 0.61). Based on a review of the final SEAS report, as well as a review of interim data from SHARP and IMPROVE-IT, FDA believes it is unlikely that ezetimibe; simvastatin or ezetimibe increase the risk of cancer or cancer-related death, although an association cannot be definitively ruled out. FDA does not advise discontinuation of therapy, but does recommend the evaluation of clinical benefit and potential risk compared to other available cholesterol-lowering medications.
Amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease) has been reported to the FDA in a higher than expected number of patients taking statins. ALS is a progressive motor neuron disorder with symptoms such as difficulty walking or standing, difficulty with fine motor skills, atrophy of tongue and hand muscles, dysphagia, dysarthria, and muscle paralysis. Due to the seriousness of ALS and the extensive use of statins, FDA further examined data from 41 long-term controlled clinical trials. The results of the review showed no increased incidence of ALS in patients treated with a statin compared with placebo. Specifically, 9 of approximately 64,000 patients treated with a statin (4.2 cases per 100,000 patient-years) and 10 of approximately 56,000 patients treated with placebo (5 case per 100,000 patient-years) were diagnosed with ALS. FDA is examining the feasibility of performing additional epidemiologic studies to further examine the incidence and clinical course of ALS in patients taking statins.
Adverse reactions occurring in >= 2% of patients receiving ezetimibe; simvastatin regardless of causality included headache (5.8%), influenza (2.3%), upper respiratory tract infection (3.6%), diarrhea (2.8%), myalgia (3.6%), and musculoskeletal pain in the extremities (2.3%). In clinical trials evaluating ezetimibe monotherapy, the discontinuation rate due to adverse events were similar to placebo. For ezetimibe monotherapy, adverse events which were reported during placebo-controlled trials (regardless of causality) included: fatigue, abdominal pain, diarrhea, viral infection, pharyngitis, sinusitis, arthralgia, back pain, and cough. Adverse reactions were similar in trials comparing ezetimibe or statin monotherapy versus ezetimibe/statin combination therapy. During controlled clinical trials involving simvastatin monotherapy atrial fibrillation, cataracts, vertigo, constipation, diarrhea, dyspepsia, flatulence, nausea, gastritis, abdominal pain, eczema, itching, rash, bronchitis, sinusitis, urinary tract infections, asthenia, and edema were reported.
Myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In general, rhabdomyolysis is a rare (less than 1/100,000 prescriptions) complication of HMG-CoA reductase inhibitor (statin) therapy. Rhabdomyolysis may occur anytime during drug treatment; however, the risk appears to be the highest during the first year of therapy. The risk is increased when ezetimibe; simvastatin is used in combination with CYP3A4 inhibitors or drugs that have an independent risk of myopathy or when the 80 mg/day dose of simvastatin is used. In clinical trials, the frequency of myopathy/rhabdomyolysis has been reported to be approximately 0.02% for 20 mg, 0.08% for 40 mg, and 0.61% for 80 mg dosing of simvastatin, respectively. Therefore, the 80 mg dose is restricted to patients who have taken simvastatin 80 mg for 12 months or greater without evidence of muscle toxicity. Patient-specific predisposing factors for myopathy include age 65 years or older, female gender, uncontrolled hypothyroidism, Chinese ethnicity, and renal dysfunction. Many cases result in hospitalization and a need for dialysis for treatment. Vigilant clinical monitoring during prescribing can help limit serious adverse events. Acute renal failure (renal tubular obstruction, myoglobinuria) have been reported rarely during simvastatin monotherapy. Rhabdomyolysis has been reported in patients taking ezetimibe in combination with an HMG Co-A reductase inhibitor. In clinical trials the incidence of creatinine phosphokinase (CK) greater than 10 X the upper limit of normal (ULN) was 0.2% for ezetimibe; simvastatin, 0.6% for placebo, 0% for ezetimibe, and 0.3% for all simvastatin doses. The incidence of myopathy (unexplained muscle weakness or pain with CK greater than 10 X the ULN) in patients with chronic kidney disease during the Study of Heart and Renal Protection (SHARP) was 0.2% for ezetimibe; simvastatin and 0.1% for placebo. In the same study, the incidence of rhabdomyolysis (myopathy with CK greater than 40 X ULN) was 0.09% for ezetimibe; simvastatin and 0.02% for placebo. Adverse reactions reported during an adolescent study indicate elevations of CK occurred in 2 (2%) of patients in the ezetimibe; simvastatin group and in no patients in the simvastatin monotherapy group. In post-marketing experience with ezetimibe, cases of myopathy, elevated creatinine phosphokinase, and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. In addition, the manufacturer states that Chinese patients taking lipid-modifying doses of niacin-containing products (niacin 1 g/day or greater) should not receive ezetimibe; simvastatin due to increased risk for myopathy. Patients receiving combined ezetimibe; simvastatin therapy should be monitored for symptoms of myopathy or rhabdomyolysis (myalgia, lethargy/drowsiness, fatigue, weakness, fever, and/or myasthenia) and CK serum concentrations; although CK concentrations correlate poorly with symptoms. Myopathy or myositis can reverse if therapy is discontinued.
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 simvastatin. 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.
Ezetimibe; simvastatin therapy can cause elevated hepatic enzymes. The frequency of consecutive elevated hepatic enzymes (3 or more times the upper limit of normal (ULN)) was 1.7% overall in ezetimibe; simvastatin treated patients during three 12 week, placebo controlled trials. The incidence was similar at 1.8% overall in long term (48 weeks) extension trials which included new patients and subjects previously treated with ezetimibe; simvastatin. The incidence of elevated hepatic enzymes appears to be dose related with 2.6% and 3.6% of patients receiving ezetimibe 10 mg; simvastatin 80 mg experiencing elevated hepatic enzymes in the 12 week and 48 week extension trials, respectively. These hepatic enzyme elevations appeared soon after initiation, were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation, brief interruption, or continuation of therapy. The incidence of consecutive elevations of hepatic enzymes (more than 3 times the ULN) in patients with chronic kidney disease during the Study of Heart and Renal Protection (SHARP) was 0.7% for ezetimibe; simvastatin and 0.6% for placebo. Increased alanine aminotransferase (ALT) was reported in 3.7% of patients receiving ezetimibe; simvastatin in clinical trials. Treatment discontinuation due to increased ALT and aspartate aminotransferase (AST) occurred in 0.9% and 0.4% of patients receiving ezetimibe; simvastatin in clinical trials, respectively. Hepatitis, jaundice, elevated hepatic enzymes (including elevations more than 5 times the ULN), cholelithiasis, cholecystitis, pancreatitis, nausea, and vomiting have been reported during postmarketing experience with ezetimibe; simvastatin. Additionally, there have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including ezetimibe; simvastatin. Assess liver enzymes prior to treatment initiation and repeat as clinically indicated if signs or symptoms of hepatic injury occur. Promptly discontinue ezetimibe; simvastatin if hepatic injury with clinical symptoms, hyperbilirubinemia, or jaundice occurs.
Thrombocytopenia and anemia have been reported through post-marketing experience for ezetimibe; simvastatin, ezetimibe, or simvastatin therapy.
During post-marketing experience of ezetimibe, simvastatin, or ezetimibe; simvastatin, hypersensitivity reactions, including anaphylactoid reactions, angioedema, pruritus, urticaria, and rash (unspecified) have been reported. Rash (unspecified) has been reported for 0.6% of patients receiving simvastatin during the 4S trial, which did not differ from placebo (0.6%). Pruritus may occur in 0.5% of patients treated with simvastatin (0.4% placebo). Alopecia has also been reported during statin therapy. A variety of general skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails) have been reported during HMG-CoA reductase inhibitor therapy. An apparent hypersensitivity syndrome has been reported rarely with HMG-CoA reductase inhibitors which has included one or more of the following features or anaphylactoid reactions: anaphylaxis, angioedema, lupus-like symptoms, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome.
An association between HMG-CoA reductase inhibitors (statins), including ezetimibe; simvastatin, 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 1.8-7.6); 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 > 1 year after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases, when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. The benefits of statin therapy far outweigh any risk of peripheral neuropathy; however, until more information is available, health care providers should be aware of this adverse effect. Rarely, there have been reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of statins. A review of available data by the FDA did not find an association between the event and a specific statin, statin dose, concomitant medication, or age of the patient. In general, post-marketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The cases did not appear to be associated with progressive or fixed dementia. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable. Other adverse neurological reactions that have been reported during statin therapy include insomnia, tremor, vertigo, and paresthesias. Depression, paresthesias, and dizziness have been reported in post-marketing surveillance with ezetimibe; simvastatin, ezetimibe, or simvastatin.
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 1.02-1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70-82 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 1.38-1.59). No difference in the risk for diabetes between statins was detected in either analysis. Because the use of statins has been associated with significant benefit for cardiovascular risk reduction and all-cause mortality at comparable rates in diabetic and non-diabetic patients , no changes to clinical practice guidelines have been recommended in either population. However, the increased risk of diabetes should be considered when initiating simvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.
Impotence (erectile dysfunction) has been reported during the post-marketing experience of ezetimibe; simvastatin. Other related adverse reactions have been reported during therapy with HMG-CoA reductase inhibitors in general, but a causal relationship has not been established with simvastatin. Sexual dysfunction including, libido decrease and impotence, and gynecomastia have been reported.
Interstitial lung disease has been reported during the postmarketing experience of ezetimibe;simvastatin.
HMG-CoA reductase inhibitors (statins), such as simvastatin, 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 simvastatin. 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.
This monograph discusses the use of the ezetimibe and simvastatin together. Consult individual drug monographs for more detailed information.
Ezetimibe; simvastatin is contraindicated in patients with acute hepatic failure or decompensated cirrhosis (hepatic decompensation). Increases in hepatic transaminases have been reported with ezetimibe; simvastatin. In most cases, increases in hepatic transaminases occurred soon after initiation, were transient, were not associated with symptoms, and resolved or improved on continued therapy or after temporary discontinuation of therapy. Marked persistent increases in hepatic transaminases have also occurred with ezetimibe; simvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including ezetimibe; simvastatin. Patients with alcoholism or those who consume substantial quantities of alcohol and/or have a history of hepatic disease (i.e., hepatitis) may be at increased risk for hepatic injury. Assess liver enzymes prior to treatment initiation and repeat as clinically indicated if signs or symptoms of hepatic injury occur. Promptly discontinue ezetimibe; simvastatin if hepatic injury with clinical symptoms, hyperbilirubinemia, or jaundice occurs.
Ezetimibe; simvastatin can cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK) levels) and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including simvastatin. The risk of myopathy, including rhabdomyolysis, is greater in patients receiving simvastatin 80 mg/day compared to lower doses or other statin therapies. Therefore, ezetimibe; simvastatin 10 mg/80 mg is restricted to patients who have taken simvastatin 80 mg/day chronically (e.g., 12 months or more) without evidence of myopathy. Myopathy and rhabdomyolysis has also been reported with postmarketing use of ezetimibe; the majority of patients received a statin prior to starting ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and ezetimibe in combination with a fibric acid derivative. Discontinue ezetimibe; simvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK elevations may resolve if ezetimibe; simvastatin is discontinued. Temporarily discontinue ezetimibe; simvastatin in those experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, hypotension, major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Risk factors for myopathy include age 65 years and older, uncontrolled hypothyroidism, renal impairment, concomitant use with certain drugs (including other lipid lowering therapies), and higher simvastatin dosage (i.e., higher risk with ezetimibe; simvastatin 10 mg/80 mg daily compared to lower doses). The risk of developing myopathy is increased when ezetimibe; simvastatin is used in combination with CYP3A4 inhibitors or drugs that have an independent risk of myopathy; some drug combinations are contraindicated for this reason. If a patient taking ezetimibe; simvastatin 10 mg/80 mg daily is prescribed an interacting drug that increases the risk of myopathy, switch to an alternate statin. Do not treat Chinese patients receiving lipid-modifying doses of niacin-containing products (1 g/day or greater of niacin) with ezetimibe/simvastatin 10 mg/80mg due to an increased risk for myopathy. Inform patients of the increased risk of myopathy and rhabdomyolysis when starting or increasing the dosage of ezetimibe; simvastatin. Instruct patients to promptly report unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever.
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 simvastatin. 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.
Because advanced age (65 years or more) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be prescribed with caution in geriatric adults. Some older adults may be more sensitive to the effects of the usual adult dosage of ezetimibe; simvastatin so individualize dosage to achieve serum lipoprotein goals. Long-term therapy with simvastatin has been used safely in geriatric patients in clinical trials, with no differences in safety compared to younger adult patients. In the 4S trial and the Heart Protection Study, there were no differences in the cardiovascular or stroke protection benefits of simvastatin between older and younger adults.
Ezetimibe; simvastatin therapy should be discontinued once pregnancy is identified in most patients. Alternatively, consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy, such as those with homozygous familial hypercholesterolemia or with established cardiovascular disease. Based on the mechanism of action, ezetimibe; simvastatin may cause fetal harm when administered to pregnant patients due to decreases in the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol. Cholesterol and other products of cholesterol biosynthesis are important for fetal development including synthesis of steroids and cell membranes. The U.S. Food and Drug Administration (FDA) completed a review of data from case series, prospective and retrospective observational cohort studies over decades of statin use in pregnant patients and concluded that these studies have not identified a drug-associated risk of major congenital malformations associated with statin use during pregnancy. In a Medicaid cohort linkage study of 1,152 statin-exposed pregnant women, no significant teratogenic effects were observed following maternal statin use during the first trimester of pregnancy after adjusting for potential confounders (i.e., maternal age, diabetes mellitus, hypertension, obesity, alcohol use, and tobacco use); the relative risk (RR) of congenital malformations was 1.07 (95% confidence interval (CI), 0.85 to 1.37). In addition, after accounting for confounders, there were no statistically significant increases in organ-specific malformations. In the study, statin treatment was started prior to pregnancy and was discontinued within the first trimester after pregnancy was detected in a majority of patients. In another cohort study of 469 patients who were dispensed statins during pregnancy, it was determined that there was no increase in congenital anomalies after adjustment for maternal age and comorbidities; however, statin use was associated with an increased risk of preterm labor (RR, 1.99 [95% CI, 1.46 to 2.71]) and low birth weight (RR, 1.51 [95% CI, 1.05 to 2.16]). In a published, retrospective cohort study of 281 statin-exposed pregnant women, patients on statin therapy had a miscarriage rate of 25% compared to 21% for pregnant women not on statin therapy (n = 2,643); adjusted hazard ratio was 1.64 (95% CI, 1.1 to 2.46). The FDA also re-reviewed non-clinical, animal data statin development programs and concluded that statins have a limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during embryofetal development during the pre- and post-natal period. Simvastatin administered to pregnant rats (doses 0.6 to 2.3 times the maximum recommended human dose [MRHD]) and rabbits (0.5 to 2 times the MRHD) did not demonstrate maternal toxicity or embryolethality; however, a decrease in mean fetal body weight was noted. There are insufficient data on ezetimibe use in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300, or 1000 mg/kg/day. Maternal toxicity or adverse developmental outcomes were not observed up to and including the highest dose tested (17 times the MRHD). Overall, available data have not identified a drug-associated risk of major congenital malformations, but published data are insufficient to determine if there is a drug-associated risk of miscarriage. Temporary discontinuation of lipid-lowering therapy, such as ezetimibe; simvastatin, should have minimal impact on the long-term therapy of primary hyperlipidemia, as atherosclerosis is a chronic process. Advise pregnant patients and patients of child-bearing potential of the potential risk of statin therapy to the fetus and the importance of informing their health care provider of known or suspected pregnancy.
Ezetimibe; simvastatin is not recommended for use during breast-feeding. There is no information about the presence of ezetimibe or simvastatin in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway. Based on the mechanism of action of ezetimibe; simvastatin, there is potential for development of serious adverse reactions in a breastfed infant. Advise patients that breast-feeding is not recommended during treatment with ezetimibe; simvastatin. If pharmacotherapy for hypercholesterolemia is necessary in the nursing mother, an alternative agent such as a nonabsorbable resin (cholestyramine, colesevelam, or colestipol) may be considered. These agents do not enter the bloodstream and will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.
The safety and efficacy of ezetimibe; simvastatin combinations have not been established in neonates, infants, children < 10 years, or in pre-pubertal females. Counsel adolescent females regarding appropriate methods of contraception while on therapy. The long-term efficacy of therapy in childhood to reduce morbidity and mortality later in adulthood has not been established. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children in not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8-10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.
Chinese patients taking lipid-modifying doses of niacin-containing products (niacin 1 g/day or greater) should not receive ezetimibe; simvastatin due to increased risk for myopathy. In a double-blind, randomized cardiovascular outcomes trial, there was an increased incidence of myopathy in Chinese patients compared with non-Chinese patients taking ezetimibe; simvastatin 10/40 mg or simvastatin 40 mg/day coadministered with extended-release niacin 2 g/day. Chinese patients may be at increased risk for myopathy; coadministration of lipid-modifying dose niacin (1 g/day or greater) with ezetimibe; simvastatin or simvastatin should be avoided in this patient population. It is unknown if this increased risk of myopathy observed in Chinese patients applies to other Asian patients.
If ezetimibe; simvastatin is initiated in a patient with diabetes, increased monitoring of blood glucose 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 simvastatin 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 1.05-1.49, 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 one or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI >= 30 kg/m2, or HbA1c > 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 0.47-0.79, p = 0.0001),nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, 0.39-1.06, p = 0.08) and total mortality (0.83, 0.64-1.07, p = 0.15), and a 28% increase in diabetes (1.28, 1.07-1.54, 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 0.33-0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, 0.21-1.03, p = 0.05) and total mortality (HR 0.78, 0.59-1.03, p = 0.08), and no increase in diabetes (HR 0.99, 0.45-2.21, 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.
Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while receiving ezetimibe; simvastatin therapy.
Use ezetimibe; simvastatin 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 simvastatin. 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 heterozygous familial hypercholesterolemia and nonfamilial hypercholesterolemia or mixed hyperlipoproteinemia as an adjunct to diet to reduce total-C, LDL-C, Apo B, triglycerides, and non-HDL-C and to increase HDL-C:
Oral dosage:
Adults: 10 mg ezetimibe/10 mg simvastatin to 10 mg ezetimibe/20 mg simvastatin PO once daily, initially, or 10 mg ezetimibe/40 mg simvastatin PO once daily for patients requiring a larger reduction in LDL-C (more than 55%). Monitor lipid concentrations after starting therapy or adjusting dose within 2 or more weeks and adjust dose if needed. Usual dose: 10 mg/day ezetimibe/10 mg/day simvastatin to 10 mg/day ezetimibe/40 mg/day simvastatin. Max: 10 mg/day ezetimibe/80 mg/day simvastatin; restrict use to patients who have been taking 10 mg/day ezetimibe/80 mg/day simvastatin chronically (e.g., 12 months or more) without evidence of muscle toxicity. Do not titrate patients unable to achieve their LDL-C goal with 10 mg/day ezetimibe/40 mg/day simvastatin to 10 mg/day ezetimibe/80 mg/day simvastatin but place on alternative LCL-C-lowering therapy that provides greater LDL-C-lowering due to increased risk of myopathy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 10 to 17 years: 10 mg ezetimibe/10 mg simvastatin to 10 mg ezetimibe/20 mg simvastatin PO once daily, initially, or 10 mg ezetimibe/40 mg simvastatin PO once daily for patients requiring a larger reduction in LDL-C (more than 55%). Monitor lipid concentrations after starting therapy or adjusting dose within 2 or more weeks and adjust dose if needed. Usual dose: 10 mg/day ezetimibe/10 mg/day simvastatin to 10 mg/day ezetimibe/40 mg/day simvastatin. Max: 10 mg/day ezetimibe/40 mg/day simvastatin. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., apheresis) or if such treatments are unavailable to reduce elevated total-C and LDL-C:
Oral dosage:
Adults: 10 mg ezetimibe/40 mg simvastatin PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
10 mg/day PO ezetimibe and 40 mg/day PO simvastatin for most patients; 80 mg/day PO simvastatin for patients already taking 80 mg/day chronically without evidence of myopathy.
-Geriatric
10 mg/day PO ezetimibe and 40 mg/day PO simvastatin for most patients; 80 mg/day PO simvastatin for patients already taking 80 mg/day chronically without evidence of myopathy.
-Adolescents
10 mg/day PO ezetimibe and 40 mg/day PO simvastatin.
-Children
>= 10 years: 10 mg/day PO ezetimibe and 40 mg/day PO simvastatin.
< 10 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Ezetimibe; simvastatin is contraindicated in patients with active hepatic disease or unexplained persistent elevations in hepatic transaminases.
Patients with Renal Impairment Dosing
CrCl >= 60 mL/min: No dosage adjustment necessary.
CrCl < 60 mL/min and chronic kidney disease: 10 mg/day PO ezetimibe and 20 mg/day PO simvastatin; higher doses should be used with caution and close monitoring.
*non-FDA-approved indication
Abrocitinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with abrocitinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; abrocitinib is a P-gp inhibitor.
Adagrasib: (Contraindicated) Concurrent use of simvastatin and adagrasib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Aluminum Hydroxide: (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: (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: (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: (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: (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.
Amiodarone: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amiodarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amiodarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amiodarone and simvastatin against the potential risks. Amiodarone increases the simvastatin exposure by approximately 2-fold.
Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Atorvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Benazepril: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Celecoxib: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Olmesartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Valsartan: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Amobarbital: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Antacids: (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: (Moderate) Use caution if simvastatin and aprepitant, fosaprepitant are used concurrently and monitor for an increase in simvastatin-related adverse effects, including myopathy and rhabdomyolysis, for several days after administration of a multi-day aprepitant regimen. Simvastatin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of simvastatin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Asciminib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with asciminib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; asciminib is an OATP1B1 inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (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: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Atazanavir; Cobicistat: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Barbiturates: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Bempedoic Acid: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 40 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and simvastatin against the potential risks. Bempedoic acid increases the simvastatin AUC and Cmax by 2-fold and 1.5-fold, respectively.
Bempedoic Acid; Ezetimibe: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking bempedoic acid due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 40 mg/day or greater who need to be started on bempedoic acid, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of bempedoic acid and simvastatin against the potential risks. Bempedoic acid increases the simvastatin AUC and Cmax by 2-fold and 1.5-fold, respectively.
Berotralstat: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with berotralstat is necessary. Simvastatin is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A 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.
Bosentan: (Moderate) Co-administration of bosentan decreases the plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite, by approximately 50%. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving simvastatin should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
Butalbital; Acetaminophen: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Butalbital; Acetaminophen; Caffeine: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Calcium Carbonate: (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: (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: (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: (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: (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: (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.
Cannabidiol: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with cannabidiol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with capmatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; capmatinib is a P-gp inhibitor.
Carbamazepine: (Minor) Carbamazepine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates, including simvastatin.
Carvedilol: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.
Ceritinib: (Contraindicated) Concurrent use of simvastatin and ceritinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
Chlorzoxazone: (Moderate) One case report has noted a possible drug interaction between simvastatin and chlorzoxazone. Rhabdomyolysis, slight renal insufficiency and cholestatic hepatitis occurred in a 73-year old woman 14 days after chlorzoxazone was added to an established simvastatin regimen. Withdrawal of chlorzoxazone combined with volume substitution and forced diuresis lead to an almost complete resolution of symptoms. As chlorzoxazone is a substrate for the CYP2E1 isozyme, and simvastatin is a substrate for the CYP3A4 isozyme, it appears unlikely that the interaction was due to metabolic interference. The authors speculate that the interaction may have occurred via chlorzoxazone-induced cholestasis which then lead to increased blood concentrations of simvastatin resulting in rhabdomyolysis and renal impairment.
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.
Ciprofloxacin: (Moderate) Monitor for evidence of myopathy, including rhabdomyolysis, during coadministration of ciprofloxacin and simvastatin. There are case reports of rhabdomyolysis in patients stabilized on a simvastatin regimen after the addition of ciprofloxacin. Ciprofloxacin may increase simvastatin exposure. Simvastatin is a substrate for CYP3A; ciprofloxacin is a moderate CYP3A inhibitor.
Clarithromycin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Cobicistat: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
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.
Conivaptan: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Simvastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
Crizotinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Cyclosporine: (Contraindicated) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1. (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.
Dabigatran: (Moderate) Consider a statin other than lovastatin or simvastatin if HMG-CoA reductase inhibition is necessary for a patient receiving dabigatran. Increased serum concentrations of dabigatran are possible when coadministered with lovastatin. If use together is medically necessary, patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. A mechanism for this interaction may be the inhibition of P-gp by simvastatin; dabigatran is a P-gp substrate. In one clinical trial, patients receiving dabigatran with lovastatin or simvastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Dabrafenib: (Major) The concomitant use of dabrafenib and simvastatin may lead to decreased simvastatin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of simvastatin efficacy. Dabrafenib is a moderate CYP3A4 inducer and simvastatin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
Daclatasvir: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
Danazol: (Contraindicated) The use of simvastatin with danazol is contraindicated due to an increased risk of myopathy and rhabdomyolysis. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism.
Danicopan: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with danicopan is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; danicopan is a P-gp inhibitor.
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.
Daridorexant: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with daridorexant is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; daridorexant is a P-gp inhibitor.
Darolutamide: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; darolutamide is an OATP1B1 inhibitor.
Darunavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Darunavir; Cobicistat: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Deferasirox: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as simvastatin. If these drugs are used together, monitor patients for a decrease in the effects of simvastatin.
Delavirdine: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when delavirdine is given in combination with HMG-CoA reductase inhibitors. Concomitant use of delavirdine and the CYP3A4 substrate simvastatin is not recommended. If treatment with an HMG-CoA reductase inhibitor is necessary, pravastatin should also be considered, since it is not significantly metabolized by CYP3A4 or CYP2C9 isoenzymes.
Digoxin: (Moderate) Simvastatin causes a slight elevation of serum digoxin levels. Simvastatin should be used cautiously in patients receiving digoxin.
Diltiazem: (Major) Do not exceed a simvastatin dose of 10 mg/day and a diltiazem dose of 240 mg/day if coadministered due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on diltiazem, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of diltiazem and simvastatin against the potential risks. Diltiazem increases the simvastatin exposure by approximately 5-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A metabolism by diltiazem.
Dronedarone: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking dronedarone due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on dronedarone, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of dronedarone and simvastatin against the potential risks. Dronedarone increases the simvastatin exposure by approximately 4-fold.
Duvelisib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with duvelisib is necessary. Coadministration may increase the exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4 and duvelisib is a moderate CYP3A4 inhibitor.
Efavirenz: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Elacestrant: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elacestrant is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; elacestrant is a P-gp inhibitor.
Elbasvir; Grazoprevir: (Moderate) The manufacturer of elbasvir; grazoprevir recommends caution during concurrent administration with simvastatin. Although this interaction has not been studied, use of these drugs together may result in elevated simvastatin plasma concentrations. Use the lowest effective simvastatin dose and monitor patients for statin-related adverse events (such as myopathy). Simvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elexacaftor is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; elexacaftor is an OATP1B1 inhibitor. (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 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 adverse reactions if eltrombopag and simvastatin are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as simvastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor.
Enasidenib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Encorafenib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate and encorafenib is an OATP1B1 inhibitor.
Erdafitinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with erdafitinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; erdafitinib is a P-gp inhibitor.
Erythromycin: (Contraindicated) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Eslicarbazepine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as simvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of simvastatin if coadministered with eslicarbazepine. Adjust the dose of simvastatin if clinically significant alterations in serum lipds are noted.
Ethotoin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Etravirine: (Moderate) The risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors. Concomitant use of etravirine and simvastatin (CYP3A4 substrate) may result in lower plasma concentrations of the HMG-CoA reductase inhibitor; dose adjustments for may be necessary.
Everolimus: (Major) Guidelines recommend avoiding coadministration of simvastatin with everolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving everolimus. In clinical trials of Zortress in kidney transplant recipients, concurrent use of simvastatin was strongly discouraged due to reported interactions between cyclosporine and simvastatin. However, the FDA-approved labeling for Afinitor states no clinically significant pharmacokinetic interaction was observed in drug interaction studies between simvastatin and Afinitor.
Fedratinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fedratinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor.
Fenofibrate: (Moderate) Fenofibrate and simvastatin should administered concomitantly only with caution. Fenofibrate may increase the risk of myopathy, rhabdomyolysis, and acute renal failure; this risk is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (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) Concomitant use of fenofibric acid and simvastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. This risk of myopathy, rhabdomyolysis, and acute renal failure is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (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.
Fexinidazole: (Major) Avoid concomitant use of simvastatin and fexinidazole and monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration is necessary. Coadministration may increase the exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A and fexinidazole is a CYP3A inhibitor.
Flibanserin: (Moderate) In a cross-over study in 12 healthy men and women, the effect of flibanserin 50 mg twice daily for 4 days on the pharmacokinetics of simvastatin 40 mg once daily was evaluated. Flibanserin increased the AUC of simvastatin, a substrate of CYP3A4, by 1.3-fold and the Cmax by 1.2-fold. The AUC and Cmax of simvastatin acid were increased by 1.5-fold and 1.4-fold, respectively.
Fluconazole: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Fluvoxamine: (Moderate) Coadministration of fluvoxamine (CYP3A4 inhibitor) and simvastatin (CYP3A4 substrate) would be expected to result in an increase in simvastatin serum concentrations. Elevation of simvastatin serum concentrations can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. Monitor patients receiving concomitant simvastatin and fluvoxamine closely for muscle pain or weakness.
Fosamprenavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Fosphenytoin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Fostamatinib: (Moderate) Monitor for simvastatin toxicities that may require simvastatin dose reduction if given concurrently with fostamatinib. Coadministration of fostamatinib with simvastatin increased the AUC by 64% and Cmax by 113%. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; simvastatin is a sensitive substrate for CYP3A4.
Fostemsavir: (Moderate) Use the lowest possible starting dose for simvastatin when administered concurrently with fostemsavir and monitor for signs of simvastatin-associated adverse events, such as rhabdomyolysis. Use of these drugs together may increase the systemic exposure of simvastatin. Simvastatin is a substrate for the transporters OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
Futibatinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; futibatinib is a P-gp inhibitor.
Gemfibrozil: (Contraindicated) The use of simvastatin with gemfibrozil is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Gemfibrozil can cause myopathy when used alone, and the risk of myopathy and rhabdomyolysis is increased by concomitant use with simvastatin. In addition, the AUC and Cmax of simvastatin are increased with concomitant gemfibrozil use. This may be due to inhibition of OATP1B1 by gemfibrozil; simvastatin is a substrate of OATP1B1. (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 simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with simvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of simvastatin. Simvastatin is a substrate of OATP1B1/3; glecaprevir is an inhibitor of OATP1B1/3. In drug interaction studies, coadministration of simvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of simvastatin. (Major) Coadministration of pibrentasvir with simvastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Coadministration may increase the plasma concentrations of simvastatin. Simvastatin is a substrate of the drug transporters OATP1B1/3; pibrentasvir is an inhibitor of OATP1B1/3. In drug interaction studies, coadministration of simvastatin with glecaprevir; pibrentasvir resulted in more than a 2-fold increase in the AUC of simvastatin.
Grapefruit juice: (Major) Large quantities of grapefruit juice are contraindicated during simvastatin therapy due to the increased risk of myopathy. Grapefruit juice contains compounds that inhibits the CYP3A4 isozyme in the gut wall. Coadministration with grapefruit juice increases the peak serum concentrations and the AUC of lovastatin and may have a similar effect on the serum concentrations of simvastatin. Grapefruit juice should be avoided or minimized in patients taking simvastatin to avoid the potential for myopathy and rhabdomyolysis.
Hydantoins: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Idelalisib: (Contraindicated) Coadministration of idelalisib, a strong CYP3A inhibitor, with simvastatin, a CYP3A substrate, is contraindicated as simvastatin toxicities, including the risk for myopathy, may be significantly increased. Consider an alternative to simvastatin.
Imatinib: (Major) Imatinib, STI-571 inhibits the metabolism of simvastatin via CYP3A4. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively. Increases in serum concentrations of simvastatin may lead to myopathy and rhabdomyolysis.
Indinavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Isavuconazonium: (Moderate) Closely monitor for evidence of myopathy, including rhabdomyolysis if simvastatin and isavuconazonium are coadministered. Concomitant use of isavuconazonium with simvastatin may result in increased serum concentrations of simvastatin. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of CYP3A4.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Isoniazid, INH; Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Itraconazole: (Contraindicated) Simvastatin is contraindicated for use during and for 2 weeks after itraconazole therapy. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as itraconazole. If therapy with itraconazole is unavoidable, simvastatin therapy must be suspended during the course of itraconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Ivacaftor: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Ivosidenib: (Moderate) Monitor for loss of efficacy of simvastatin during coadministration of ivosidenib; a simvastatin dose adjustment may be necessary. Simvastatin is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased simvastatin concentrations.
Ketoconazole: (Contraindicated) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
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.
Lasmiditan: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with lasmiditan is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; lasmiditan is a P-gp inhibitor.
Lefamulin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oral lefamulin is necessary. Simvastatin is a sensitive CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin.
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.
Lenacapavir: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with lenacapavir is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a CYP3A and P-gp substrate and lenacapavir is a moderate CYP3A and P-gp inhibitor.
Leniolisib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with leniolisib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; leniolisib is an OATP1B1 inhibitor.
Letermovir: (Major) Use of simvastatin with letermovir is not recommended due to increased simvastatin exposure. Concurrent use is contraindicated if the patient is also receiving cyclosporine. Administering letermovir with simvastatin significantly increases simvastatin concentration and risk for myopathy or rhabdomyolysis. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Simvastatin is a sensitive substrate of CYP3A4 and the organic anion-transporting polypeptide (OATP1B1). Both letermovir and cyclosporine are moderate CYP3A4 inhibitors and inhibitors of OATP1B1.
Levamlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Levoketoconazole: (Contraindicated) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Lomitapide: (Major) Reduce the simvastatin dose by 50% when starting lomitapide due to an increased risk for myopathy, including rhabdomyolysis. In patients taking lomitapide, do not exceed a simvastatin dose of 20 mg/day in general, or 40 mg/day in patients who have previously tolerated simvastatin 80 mg/day for at least 1 year without evidence of muscle toxicity. For patients chronically receiving simvastatin 80 mg/day who need to be started on lomitapide, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of lomitapide and simvastatin against the potential risks. Lomitapide increases the simvastatin exposure by approximately 2-fold.
Lonafarnib: (Contraindicated) Coadministration of simvastatin and lonafarnib is contraindicated due to the risk of elevated plasma concentrations of simvastatin leading to myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and a P-gp substrate; lonafarnib is a strong CYP3A4 and P-gp inhibitor.
Lopinavir; Ritonavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Lumacaftor; Ivacaftor: (Moderate) Monitor for reduced efficacy of simvastatin if coadministered with lumacaftor; ivacaftor. Lumacaftor; ivacaftor may reduce the systemic exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Moderate) Monitor for reduced efficacy of simvastatin if coadministered with lumacaftor; ivacaftor. Lumacaftor; ivacaftor may reduce the systemic exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
Magnesium Hydroxide: (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: (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 simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with maribavir is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; maribavir is a P-gp inhibitor.
Metformin; Repaglinide: (Moderate) Coadministration of may lead to an increase in repaglinide. This interaction could result in an increased risk of adverse effects associated with repaglinide, specifically hypoglycemia.
Methohexital: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Midostaurin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; midostaurin is an OATP1B1 inhibitor.
Mifepristone: (Contraindicated) When mifepristone is used in the treatment of Cushing's syndrome, coadministration is contraindicated based on studies demonstrating significant simvastatin exposure increases which may lead to an increased risk of myopathy and rhabdomyolysis. Consider interruption of simvastatin therapy during use of mifepristone for pregnancy termination. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Mifepristone is a strong CYP3A inhibitor; simvastatin is a sensitive CYP3A substrate. Coadministration of mifepristone and simvastatin increased simvastatin and simvastatin acid exposure by 10.4-fold and 15.7-fold, respectively, in drug interaction studies.
Mitapivat: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with mitapivat is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; mitapivat is a P-gp inhibitor.
Mitotane: (Moderate) Use caution if mitotane and simvastatin are used concomitantly, and monitor for decreased efficacy of simvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and simvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simvastatin.
Nanoparticle Albumin-Bound Sirolimus: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
Nefazodone: (Contraindicated) Nefazodone is contraindicated during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of simvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with simvastatin.
Nelfinavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Neratinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as simvastatin. The plasma concentrations of simvastatin can increase when coadministered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Nevirapine: (Moderate) Monitor for reduced cholesterol-lowering efficacy of simvastatin if coadministration with nevirapine is necessary; a dose adjustment may be needed. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Niacin, Niacinamide: (Major) There is no clear indication for routine use of niacin in combination with simvastatin. 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 simvastatin. 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 simvastatin immediately if myopathy is diagnosed or suspected. Coadministration is not recommended in Chinese patients, as the risk of myopathy is greater in this population. It is unknown if this risk applies to other Asian patients.
Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including simvastatin.
Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and simvastatin is contraindicated. Discontinue use of simvastatin at least 12 hours before, during, and 5 days after treatment with ritonavir-boosted nirmatrelvir. Coadministration may increase simvastatin exposure resulting in increased toxicity. Simvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Nirogacestat: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with nirogacestat is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Omeprazole; Sodium Bicarbonate: (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.
Oxcarbazepine: (Minor) Oxcarbazepine which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including simvastatin. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are coadministered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
Pacritinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pacritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; pacritinib is a P-gp inhibitor.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and simvastatin, a CYP3A4 substrate, may cause an increase in systemic concentrations of simvastatin. Use caution when administering these drugs concomitantly.
Pentobarbital: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Perindopril; Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with simvastatin. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Phenobarbital: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Phenytoin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Pirtobrutinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and simvastatin is contraindicated due to the risk of myopathy, rhabdomyolysis, and acute renal failure. If therapy with posaconazole is unavoidable, simvastatin therapy must be suspended during the course of posaconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Pretomanid: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pretomanid is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; pretomanid is a P-gp inhibitor.
Primidone: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
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.
Propafenone: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Propranolol: (Minor) After administration of single doses of simvastatin and propranolol, there was a significant decrease in mean Cmax, with no change in AUC, of simvastatin. The clinical significance of this interaction is unknown. Monitor for potential reduced cholesterol-lowering efficacy when propranolol is coadministered with niacin; simvastatin.
Protease inhibitors: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Quinine: (Moderate) Patients receiving concomitant simvastatin and quinine should be monitored closely for muscle pain or weakness. Simvastatin is a CYP3A4 substrate; therefore, quinine has the potential to inhibit the metabolism of simvastatin leading to an increased potential of rhabdomyolysis. Lower starting doses of simvastatin should be considered while patients are receiving quinine. Discontinue simvastatin if marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values greater than 10 times the upper limit of normal) is diagnosed or suspected.
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).
Ranolazine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
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.
Repaglinide: (Moderate) Coadministration of may lead to an increase in repaglinide. This interaction could result in an increased risk of adverse effects associated with repaglinide, specifically hypoglycemia.
Resmetirom: (Major) Limit the dose of simvastatin to 20 mg once daily during concomitant use with resmetirom. Concomitant use was observed to increase simvastatin overall exposure by 1.7-fold which may increase the risk for simvastatin-related adverse effects.
Ribociclib: (Contraindicated) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
Ribociclib; Letrozole: (Contraindicated) Concurrent use of simvastatin and ribociclib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
Rifabutin: (Minor) Rifabutin may induce the CYP3A4 metabolism of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Rifampin: (Moderate) Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and simvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Ritlecitinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with ritlecitinib is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Saquinavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Sarilumab: (Moderate) Utilize caution with concomitant use of sarilumab and CYP3A4 substrate drugs, such as simvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. A 45% decrease in simvastatin exposure was noted 1 week after a single sarilumab dose. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Simvastatin is a CYP3A4 substrate.
Secobarbital: (Moderate) Barbiturates are significant hepatic CYP3A4 inducers. Monitor for potential reduced cholesterol-lowering efficacy when barbiturates are co-administered with simvastatin, which is metabolized by CYP3A4.
Selpercatinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with selpercatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; selpercatinib is a P-gp inhibitor.
Siltuximab: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as simvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
Sirolimus: (Major) Guidelines recommend avoiding coadministration of simvastatin with sirolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving sirolimus.
Sodium Bicarbonate: (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 simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with taurursodiol is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; taurursodiol is a P-gp inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of velpatasvir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate of OATP1B1/3; velpatasvir is an inhibitor of OATP1B1/3.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of velpatasvir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate of OATP1B1/3; velpatasvir is an inhibitor of OATP1B1/3. (Moderate) Initiate simvastatin at the lowest approved dose if coadministration of voxilaprevir is necessary due the potential for increased simvastatin exposure and risk for adverse events, such as myopathy or rhabdomyolysis. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Simvastatin is a substrate OATP1B1; voxilaprevir is an inhibitor of OATP1B1.
Sotorasib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; sotorasib is a P-gp inhibitor.
Sparsentan: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sparsentan is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; sparsentan is a P-gp inhibitor.
St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, CYP1A2, and potentially CYP2C9. Co-administration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including simvastatin.
Stiripentol: (Moderate) Consider a dose adjustment of simvastatin when coadministered with stiripentol. Coadministration may alter plasma concentrations of simvastatin resulting in an increased risk of adverse reactions and/or decreased efficacy. Simvastatin is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
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: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
Telmisartan; Amlodipine: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Tepotinib: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with tepotinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; tepotinib is a P-gp inhibitor.
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.
Tesamorelin: (Moderate) Use caution when coadministering tesamorelin with simvastatin as their concurrent use may alter simvastatin plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with simvastatin resulted in an 8% decrease in simvastatin AUC and a 5% increase in simvastatin Cmax. The clinical impact of these pharmacokinetic changes are unknown; however, patients should be monitored for decreased simvastatin efficacy. Further, since simvastatin is a substrate for CYP3A4, it may be theorized that tesamorelin has little impact on CYP3A activity.
Tezacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Ticagrelor: (Moderate) Avoid simvastatin doses above 40 mg/day PO when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of simvastatin. Simvastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
Tipranavir: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Tocilizumab: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as simvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Simvastatin is a CYP3A4 substrate.
Trandolapril; Verapamil: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A metabolism and reduction of first-pass metabolism by verapamil.
Trofinetide: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; trofinetide is an OATP1B1 inhibitor.
Tucatinib: (Contraindicated) Concurrent use of simvastatin and tucatinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Verapamil: (Major) Do not exceed a simvastatin dose of 10 mg/day in patients taking verapamil due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of verapamil and simvastatin against the potential risks. Verapamil increases the simvastatin exposure by approximately 2-fold. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A metabolism and reduction of first-pass metabolism by verapamil.
Viloxazine: (Moderate) Monitor for an increase in simvastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase simvastatin exposure; viloxazine is a weak CYP3A inhibitor and simvastatin is a CYP3A substrate.
Vitamin B Complex Supplements: (Major) There is no clear indication for routine use of niacin in combination with simvastatin. 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 simvastatin. 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 simvastatin immediately if myopathy is diagnosed or suspected. Coadministration is not recommended in Chinese patients, as the risk of myopathy is greater in this population. It is unknown if this risk applies to other Asian patients.
Voclosporin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voclosporin is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; voclosporin is a P-gp and OATP1B1 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Voriconazole: (Contraindicated) Concurrent use of simvastatin and voriconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as voriconazole. If therapy with voriconazole is unavoidable, simvastatin therapy must be suspended during voriconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Voxelotor: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voxelotor is necessary. Simvastatin is a sensitive CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (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. (Moderate) Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Zafirlukast: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin exhibit synergistic mechanisms that reduce elevated serum total-C, LDL-C, Apo B, TG, and non-HDL-C concentrations and increase serum HDL-C concentrations through inhibition of cholesterol absorption and synthesis. The effects of combined therapy with ezetimibe and HMG-CoA reductase inhibitors ('statins') result in greater LDL reductions and therapeutic benefit than either ezetimibe or statin monotherapy. When used in combination with 10-80 mg of either simvastatin, combined use with ezetimibe achieved LDL-reductions of approximately > 51% compared to 36% with simvastatin monotherapy.
-Ezetimibe: Ezetimibe has a mechanism of action that is unique compared to other available antilipemic agents. 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 excretion. Ezetimibe localizes and appears to act at the brush border of the small intestine. It 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. 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. In humans, the effects of ezetimibe to reduce triglycerides (TG) (8%) or to lower HDL-cholesterol (1%) are less prominent than the LDL-lowering effects; ezetimibe therapy usually increases HDL-C levels. In animal models (rodents), ezetimibe reduces the cholesterol content in chylomicrons without affecting the triglyceride content. In rodents, ezetimibe has no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins (A, D, and E), and does not impair adrenocortical steroid hormone production.
-Simvastatin: Like lovastatin, simvastatin is a prodrug with little or no inherent activity. The 6-membered lactone ring is hydrolyzed in vivo to generate mevinolinic acid. Mevinolinic acid, one of simvastatin's several active metabolites, is structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol can also be taken up from LDL by endocytosis. Since de novo synthesis of cholesterol is impaired by simvastatin, cholesterol uptake is augmented. Thus, simvastatin also enhances clearance of LDL. Simvastatin decreases serum total cholesterol (serum total-C), LDL-cholesterol, VLDL, triglycerides (TG), and apolipoprotein B (Apo-B), while increasing HDL-C. Simvastatin is administered in the evening hours since there is evidence for diurnal variation in the hepatic synthesis of cholesterol. HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.
The combination of ezetimibe; simvastatin is administered orally. No clinically significant pharmacokinetic interactions have been noted when ezetimibe was co-administered with the HMG-CoA reductase inhibitors studied (e.g., simvastatin). Concomitant administration of ezetimibe has no significant effect on the bioavailability of these statins; the bioavailability of total ezetimibe is also unaffected. The ezetimibe; simvastatin product is bioequivalent to the drugs coadministered separately.
-Ezetimibe: Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins. Following absorption, 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 co-administration has no significant effect on specific probe drugs known to be metabolized by cytochrome P-450 enzymes (CYP1A2, CYP2D6, CYP2C8/9 and CYP3A4 isoenzymes). In addition, cimetidine (a non-specific cytochrome P-450 inhibitor) has no effect on the bioavailability of ezetimibe or total ezetimibe. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10-20% and 80-90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life (T1/2) of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. Following 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.
-Simvastatin: Simvastatin is an inactive prodrug. It is the methylated derivative of lovastatin and, like lovastatin, must be activated in the liver. Both simvastatin and the active metabolite are strongly bound to plasma proteins (95%). Simvastatin and lovastatin are lipophilic, while pravastatin is hydrophilic. Being lipophilic, simvastatin is taken up by cells other than hepatocytes and, unlike pravastatin, simvastatin penetrates the CNS. Sixty percent of an oral dose is excreted in the feces and 13% in the urine. The half-life (T1/2) of simvastatin is 1.9 hours
-Route-Specific Pharmacokinetics
Oral Route
-Ezetimibe: The absolute bioavailability of ezetimibe is not known. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, co-administration with a high-fat meal increases the peak concentration (Cmax) of ezetimibe by 38%.
-Simvastatin: Absorption is about 85%, but bioavailability is less than 5%. Absorption is not significantly reduced if taken before a low-fat meal; the drug can be administered with or without food. To optimize the action of simvastatin, it should be administered in the evening hours or at bedtime. Peak plasma concentrations are reached in 1.3-2.4 hours.
-Special Populations
Hepatic Impairment
-Ezetimibe: Pharmacokinetic differences for ezetimibe have been identified in patients with mild hepatic impairment; however, no dosage adjustments for ezetimibe are indicated. Significant increases in ezetimibe exposure (AUC) occur in patients with moderate to severe hepatic impairment.
Renal Impairment
-Ezetimibe: After a single 10 mg dose of ezetimibe in patients with severe renal disease (n = 8; mean CrCl <= 30 mL/min), the mean AUC for total ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n = 9).
-Simvastatin: Although pharmacokinetic data are lacking for simvastatin in patients with severe renal impairment (CrCl <= 30 mL/min), data for a related HMG-CoA reductase inhibitor (lovastatin) suggests the need for cautious dosage escalation in such patients, since higher systemic exposure (AUC) is expected.
Geriatric
-Ezetimibe: Pharmacokinetic differences for ezetimibe have been identified in elderly patients; however, no dosage adjustments for ezetimibe are indicated.
-Simvastatin: A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients aged 70-78 years as compared with younger adults.
Gender Differences
-Ezetimibe: Pharmacokinetic differences for ezetimibe have been identified in women; however, no dosage adjustments for ezetimibe are indicated.