Atorvastatin is a selective, competitive HMG-CoA reductase inhibitor. It is primarily used to lower cholesterol and triglycerides in patients with hypercholesterolemia and mixed dyslipidemia, and may also be used for homozygous familial hypercholesterolemia. At the maximum recommended dosage, it has greater LDL-lowering efficacy relative to the maximum recommended dosage of other HMG-CoA reductase inhibitors; this may be explained by it's unique structure, long half-life, and hepatic selectivity. In a dose-dependent manner, atorvastatin lowers LDL cholesterol by as much as 60%; oral doses as low as 2.5 mg/day were as effective as lower doses of other HMG-CoA reductase inhibitors. Doses of 10 to 80 mg daily result in mean LDL reductions ranging from 43-60%. Triglycerides are lowered in patients with hypertriglyceridemia by as much as 45% and HDL increases by as much as 12% with monotherapy. Administration with colestipol produced a 10% greater reduction in LDL-cholesterol than atorvastatin alone, however, adverse reactions were greater and compliance was lower for the combination. Clinical outcome trials have demonstrated benefits in various populations including the patients treated for the first several months following acute coronary syndromes (MIRACLE) , high-risk hypertensives (ASCOT-LLA) , and type 2 diabetics (CARDS trial) . Trials have demonstrated beneficial cardiovascular outcomes of intensive LDL-lowering utilizing 80 mg once daily relative to moderate LDL-lowering regimens such as pravastatin 40 mg daily (PROVE-IT trial) or atorvastatin 10 mg daily (TNT trial). The TNT trial demonstrated reduced cardiovascular events with 80 mg versus 10 mg daily in patients with stable coronary heart disease (CHD). In addition, post-hoc analysis of data from the TNT trial show that patients with previous coronary artery bypass grafting (CABG) surgery who received 80 mg daily had a decreased risk of cardiovascular events and need for repeat coronary revascularization compared with those who received 10 mg. The IDEAL trial reported no significant difference in rate of all-cause mortality or first coronary event in patients with a history of CHD who received atorvastatin 80 mg versus simvastatin 20-40 mg once daily. However, a large retrospective study demonstrated that continuation of statin therapy provides an ongoing reduction in all-cause mortality in patients with and without known CHD, with the greatest risk reduction among patients with a baseline LDL-C >= 190 mg/dl and patients initiated on higher efficacy statins (i.e., simvastatin, pravastatin, or lovastatin 80 mg/day; atorvastatin >= 20 mg/day; rosuvastatin >= 10 mg/day). Among patients with a proportion of days covered (PDC) of >= 90%, determined by the number of statin prescriptions dispensed during the time between the first statin prescription and the end of follow up, there was a 45% and 51% lower mortality risk in the primary (patients without known CHD) and secondary (patients with known CHD) prevention groups, respectively, compared to patients with a PDC <= 10%. The mean length of follow up was 4 and 5 years in the primary and secondary prevention groups, respectively, with a maximum follow up of 9.5 years. Aggressive lipid lowering with atorvastatin 80 mg/day was at least as effective as angioplasty and usual care in reducing the incidence of ischemic events in patients with stable coronary artery disease. Aggressive lipid-lowering with atorvastatin 80 mg/day also improved clinical outcomes compared to usual care in patients with CHD in a managed care patient population. Short term pretreatment with intensive lipid-lowering doses of atorvastatin (80 mg/day) also may improve outcomes in patients with ACS undergoing early invasive strategy. In addition, intensive lipid-lowering with 80 mg/day has also been shown to reduce the progression of coronary, carotid, and/or femoral atherosclerosis in clinical trials (REVERSAL, ARBITER, and ASAP studies). The SATURN trial reported no statistically significant difference between atorvastatin 80 mg daily and rosuvastatin 40 mg daily on the progression of atherosclerosis in high risk patients measured by change from baseline in percent atheroma volume in a >= 40 mm segment of the targeted coronary artery as assessed by intravascular ultrasound. There was, however, a statistically significant difference in total atheroma volume within the targeted coronary artery in favor of rosuvastatin. The initial FDA approval for atorvastatin to treat hypercholesterolemia and mixed dyslipidemia was granted in December 1996. Indications were subsequently expanded to include prevention of cardiovascular events in patients with clinically evident CHD and patients without clinical evidence of CHD, but with multiple risk factors for CHD.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Patients receiving atorvastatin therapy should also be placed on a standard cholesterol-lowering diet, and this diet should be continued throughout therapy. Serum lipoprotein concentrations should be determined periodically and dosage adjusted according to individual response and established NCEP treatment guidelines.
Route-Specific Administration
Oral Administration
-Administer atorvastatin once daily at any time during the day. Nighttime administration, as is recommended with some other agents, is not necessary.
-Missed dose: Instruct patients to take a missed dose as soon as possible. If a dose is missed by more than 12 hours, skip the missed dose and resume with the next scheduled dose.
Oral Solid Formulations
Tablets:
-Atorvastatin tablets may be taken with or without food.
Oral Liquid Formulations
Oral suspension:
-Measure atorvastatin suspension doses using a calibrated oral syringe or other oral dosing device scored using metric units of measurement (i.e., mL).
-Administer atorvastatin suspension on an empty stomach (1 hour before or 2 hours after a meal).
-Storage: Discard any unused suspension after 60 days of first opening the bottle.
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.
The most frequent gastrointestinal adverse reactions occurring in patients treated with atorvastatin during placebo-controlled trials include dyspepsia (3.2 to 6% vs. 4.3%), diarrhea (5.2% to 14.1% vs. 6.3%), and nausea (3.7% to 7.1% vs. 3.5%). Abdominal pain, eructation, and flatulence have also been reported in adult patients receiving atorvastatin in placebo-controlled trials.
The most frequent central nervous system (CNS) adverse reaction reported by patients treated with atorvastatin during placebo-controlled trials was insomnia (1.1 to 5.3% vs. 2.9%). Rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with the use of statins. A review of available data by the FDA did not find an association between the event and a specific statin, statin dose, concomitant medication, or age of the patient. In general, post-marketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The cases did not appear to be associated with progressive or fixed dementia. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable. Other CNS adverse events reported during clinical trials with atorvastatin include nightmares, fever, and malaise (each less than 2% incidence). Depression, dizziness, and fatigue have been reported in the postmarketing use of atorvastatin.
Atorvastatin can cause myopathy (muscle pain, muscle tenderness, or muscle weakness (myasthenia) associated with elevated creatine kinase (CK) levels) and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin. Discontinue atorvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain drugs (including other lipid lowering therapies), and higher atorvastatin dosage. Monitor all patients with renal impairment for increased risk of myopathy. During clinical trials, myalgia occurred in 3.5% (2.7 to 8.4%) of patients taking atorvastatin vs. 3.1% of patients receiving placebo. Other frequent musculoskeletal adverse reactions occurring in adult patients during placebo-controlled trials were muscle spasms (2.4 to 5.1% vs. 3%), musculoskeletal pain (2.3% to 5.2% vs. 3.6%), pain in the extremity (3.1% to 9.3% vs. 5.9%), arthralgia (4.3% to 11.7% vs. 6.5%), muscle fatigue, neck pain, and joint swelling. Tendon rupture and myositis have been reported with postmarketing use.
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 atorvastatin. 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.
Increases in hepatic transaminases have been reported with atorvastatin. In most cases, these changes appeared soon after initiation, were transient, were not associated with symptoms, and resolved or improved on continued therapy or after temporary discontinuation of therapy. Consider assessing liver function tests (LFTs) prior to initiation of atorvastatin and then repeat as clinically indicated thereafter. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, promptly discontinue therapy. During clinical trials, 0.7% of patients developed persistent elevated hepatic enzymes while receiving atorvastatin. The incidence of transaminase elevations was dose-related with persistent elevations occurring in 0.2%, 0.2%, 0.6%, and 2.3% of patients receiving 10, 20, 40, and 80 mg, respectively. One patient in clinical trials with atorvastatin developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin. Hepatitis and cholestasis have been reported in adult individuals receiving atorvastatin in placebo-controlled trials. Pancreatitis and hepatic failure (fatal and non-fatal) have been reported with use of atorvastatin in postmarketing reports.
Tinnitus, blurred vision, and epistaxis have been reported during clinical trials with atorvastatin (incidence not reported).
Dermatological and hypersensitivity events rarely reported during post-marketing experience with atorvastatin, regardless of causality, include: anaphylaxis, angioedema, angioneurotic edema, bullous rash, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Urticaria has been reported in patients receiving atorvastatin in placebo-controlled trials. 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 rarely been reported 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 atorvastatin, and peripheral neuropathy has been reported in the literature (case series, case-control studies, cohort studies). In a nested case-control study of a Danish population, the odds ratio for idiopathic peripheral neuropathy in 166 patients that ever or were currently taking a statin, was 3.7 (95% CI 1.8 to 7.6); similar results have been found in other population based studies, although the number of patients studied was significantly smaller. Case reports and series indicate that the onset of neuropathy is typically greater than 1 year after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases, when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. Peripheral neuropathy was reported with postmarketing use of atorvastatin.
Diabetes mellitus and hyperglycemia have been reported with the use of atorvastatin. In the SPARCL trial, diabetes was reported in 6.1% of patients in the atorvastatin group compared to 3.8% in the placebo. A meta-analysis of 13 statin trials with 91,140 participants showed a slight increase in the risk of the development of diabetes mellitus in statin-treated patients compared to patients taking a control. During a mean statin exposure of 4 years, 174 more cases of incident diabetes were reported in the patients assigned to statin therapy than in the patients receiving placebo or standard-care, which represents a 9% increase in the likelihood of the development of diabetes (OR 1.09. 95% CI 1.02 to 1.17) or 1 additional case of diabetes for every 255 patients taking statin therapy. The risk of incident diabetes associated with statin therapy was stronger in older patients; there was no difference in the risk for diabetes between statins. The occurrence of diabetes was lowest in the primary prevention trials, which consisted of patients with low diabetes risk (i.e., low BMI); the risk was highest in trials that included high-risk patients (i.e., age 70 to 82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure). Because the absolute risk for the development of diabetes is low and is outweighed by the benefit of statins for cardiovascular risk reduction, no change to clinical practice is recommended in patients at moderate or high risk for cardiovascular disease or those with existing cardiovascular disease. However, the increased risk of diabetes should be considered when initiating statin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.
A higher incidence of hemorrhagic stroke was seen in patients receiving atorvastatin 80 mg/day PO compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168) in a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. SPARCL consisted of 4731 subjects without CHD who had a stroke or transient ischemic attack (TIA) within the previous 6 months who were administered atorvastatin 80 mg/day PO or placebo. The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). However, the incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) compared to the placebo group (16, 0.7%). The risk of hemorrhagic stroke was increased in those having hemorrhagic stroke as the qualifying study entry event (HR 5.65, 95% CI 2.82 to 11.30, p less than 0.001), males (HR 1.79, 95% CI 1.13 to 2.84, p = 0.01), and those with increasing age (10 year increments, HR 1.42, 95% CI 1.16 to 1.74, p = 0.001). Additionally, patients having stage 2 hypertension (defined by JNC-7) at the last study visit prior to a hemorrhagic stroke were also at increased risk (HR 6.19, 95% CI 1.47 to 26.11, p = 0.01). There was no relationship between the risk of hemorrhagic stroke and baseline or recent LDL level in atorvastatin-treated patients.
As reported in the product labeling, the most frequent infectious or respiratory adverse reactions occurring in patients treated with atorvastatin during placebo-controlled trials are urinary tract infection (5.7% vs. 5.6%), naso-pharyngitis (8.3% vs. 8.2%), and pharyngolaryngeal pain (2.3% vs. 2.1%). Fever has also been reported in adult patients receiving atorvastatin in placebo-controlled trials. Interstitial lung disease has been reported with the postmarketing use of atorvastatin.
HMG-CoA reductase inhibitors (statins), such as atorvastatin, inhibit the synthesis of mevalonate and decrease Co-Enzyme Q-10 concentrations, which may lead to Co-Enzyme Q-10 deficiency. Supplementation with vitamin Co-Enzyme Q-10 may limit potential adverse reactions.
Exacerbation and induction of myasthenia gravis has been reported during treatment with statins, including atorvastatin. In a review of 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%) 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.
Atorvastatin is contraindicated in patients with atorvastatin hypersensitivity or hypersensitive to any components of the product selected.
Atorvastatin is contraindicated in patients with acute hepatic failure or decompensated cirrhosis. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol (alcoholism) and/or have a history of hepatic disease. Increases in hepatic transaminases have been reported with atorvastatin. 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. Persistent increases of more than three times the upper limit of normal in hepatic transaminases have occurred in approximately 0.7% of patients receiving atorvastatin in clinical trials. Consider assessing liver enzyme tests prior to initiation of atorvastatin and repeat as clinically indicated thereafter. Elevated hepatic transaminases have been reported in patients receiving HMG-CoA reductase inhibitors; these abnormalities were not associated with cholestasis and did not appear to be associated with treatment duration. After extensive data review, the FDA concluded that the risk of serious liver injury is very low and routine periodic monitoring of liver enzymes has not been effective in detection or prevention of serious hepatic injury. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, discontinue atorvastatin.
Atorvastatin 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 atorvastatin. Discontinue atorvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic disorders, severe endocrine disease, severe electrolyte imbalance, or uncontrolled seizure disorder). Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain drugs (including other lipid lowering therapies), and higher atorvastatin dosage. Monitor all patients with renal impairment for increased risk of myopathy. Atorvastatin levels may be increased when coadministered with medications that inhibit cytochrome P450 enzyme 3A4 and/or transporters (breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3], and p-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Consumption of large quantities of grapefruit juice (greater than 1.2 L/day) is not recommended. Inform patients of the risk of myopathy and rhabdomyolysis when initiating or increasing the dosage of atorvastatin. 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 atorvastatin. 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.
Increased hemoglobin A1C, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Optimization of lifestyle measures, including regular exercise, maintaining a healthy body weight and making healthy food choices are recommended. If atorvastatin is initiated in a patient with diabetes mellitus, increased monitoring of blood glucose control may be warranted. 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 atorvastatin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established. Although an analysis of participants from the JUPITER trial found an increased incidence of developing diabetes in patients allocated to rosuvastatin compared to placebo (270 reports of diabetes vs. 216 in the placebo group; HR 1.25, 95% CI 1.05 to 1.49, p = 0.01), the cardiovascular and mortality benefits of statin therapy exceeded the diabetes hazard even in patients at high risk for developing diabetes (i.e., patients with 1 or more major diabetes risk factor: metabolic syndrome, impaired fasting glucose, BMI 30 kg/m2 or more, or A1C more than 6%). In patients at high risk for developing diabetes, treatment with rosuvastatin was associated with a 39% reduction in the primary endpoint (composite of non-fatal myocardial infarction, non-fatal stroke, unstable angina or revascularization, and cardiovascular death) (HR 0.61, 95% CI 0.47 to 0.79, p = 0.0001), nonsignificant reductions in venous thromboembolism (VTE) (HR 0.64, CI 0.39 to 1.06, p = 0.08) and total mortality (HR 0.83, CI 0.64 to 1.07, p = 0.15), and a 28% increase in diabetes (HR 1.28, CI 1.07 to 1.54, p = 0.01). In patients with no major diabetes risk factor, treatment with rosuvastatin was associated with a 52% reduction in the primary endpoint (HR 0.48, 95% CI 0.33 to 0.68, p = 0.0001), nonsignificant reductions in VTE (HR 0.47, CI 0.21 to 1.03, p = 0.05) and total mortality (HR 0.78, CI 0.59 to 1.03, p = 0.08), and no increase in diabetes (HR 0.99, CI 0.45 to 2.21, p = 0.99). For those at high risk for developing diabetes, 134 total cardiovascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. In those without major risk factors, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.
Atorvastatin therapy should be discontinued once pregnancy is identified in most patients. Alternatively, consider the ongoing therapeutic needs of the individual patient. Based on the mechanism of action, atorvastatin may cause fetal harm when administered to pregnant patients due to decreases in the synthesis of cholesterol and possibly other biologically active substances derived from cholesterol. Cholesterol and other products of cholesterol biosynthesis are important for fetal development including synthesis of steroids and cell membranes. Treatment of hyperlipidemia during pregnancy is not generally necessary as atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have minimal impact on the outcome of long-term therapy of primary hypercholesterolemia. The U.S. Food and Drug Administration (FDA) completed a review of data from case series, prospective and retrospective observational cohort studies over decades of statin use in pregnant patients and concluded that these studies have not identified a drug-associated risk of major congenital malformations associated with statin use during pregnancy. In a Medicaid cohort linkage study of 1,152 statin-exposed pregnant women, no significant teratogenic effects were observed following maternal statin use during the first trimester of pregnancy after adjusting for potential confounders (i.e., maternal age, diabetes mellitus, hypertension, obesity, alcohol use, and tobacco use); the relative risk (RR) of congenital malformations was 1.07 (95% confidence interval (CI), 0.85 to 1.37). In addition, after accounting for confounders, there were no statistically significant increases in organ-specific malformations. In the study, statin treatment was started prior to pregnancy and was discontinued within the first trimester after pregnancy was detected in a majority of patients. In another cohort study of 469 patients who were dispensed statins during pregnancy, it was determined that there was no increase in congenital anomalies after adjustment for maternal age and comorbidities; however, statin use was associated with an increased risk of preterm labor (RR, 1.99 [95% CI, 1.46 to 2.71]) and low birth weight (RR, 1.51 [95% CI, 1.05 to 2.16]). In a published, retrospective cohort study of 281 statin-exposed pregnant women, patients on statin therapy had a miscarriage rate of 25% compared to 21% for pregnant women not on statin therapy (n = 2,643); adjusted hazard ratio was 1.64 (95% CI, 1.1 to 2.46). The FDA also re-reviewed non-clinical, animal data statin development programs and concluded that statins have a limited potential to cause malformations or embryofetal lethality, and limited potential to affect nervous system development during embryofetal development during the pre- and post-natal period. Decreased postnatal growth and development delay were observed in pregnant rats administered atorvastatin at doses 6 times and greater during gestation and lactation. Overall, available data have not identified a drug-associated risk of major congenital malformations, but published data are insufficient to determine if there is a drug-associated risk of miscarriage. Advise pregnant patients and patients of child-bearing potential of the potential risk of statin therapy to the fetus and the importance of informing their health care provider of known or suspected pregnancy.
Atorvastatin is not recommended for use during breast-feeding. There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, it has been shown that another medication in the same class passes into human milk. It is likely that atorvastatin is excreted to some degree in human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. 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 atorvastatin, there is potential for development of serious adverse reactions in a breastfed infant. Advise patients that breastfeeding is not recommended during treatment with atorvastatin. 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.
Safety and efficacy of atorvastatin have not been established in infants and children younger than 10 years of age. 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 is not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8 to 10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.
Since advanced age (65 years or more) is a predisposing risk factor for myopathy and rhabdomyolysis, atorvastatin should be prescribed with caution in the geriatric patient. Dose selection for geriatric patients should be cautious due to the greater frequency of decreased hepatic, renal, or cardiac function and concomitant diseases or other drug therapy in addition to higher risk of myopathy. During clinical trials, no overall differences in safety or effectiveness were observed and other reported clinical experience has not identified differences in clinical responses between elderly and younger adult patients. Plasma concentrations of atorvastatin are higher (about 40% for Cmax and 30% for AUC) in healthy elderly subjects than in young adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, HMG-CoA reductase inhibitors may impair liver function, and liver function monitoring should occur consistent with individual manufacturer recommendations (e.g., baseline, 12 weeks after initiation, after any dose increase, and periodically thereafter). HMG-CoA reductase inhibitors may cause myalgia, myopathy, and rhabdomyolysis that can precipitate kidney failure, particularly in combination with other cholesterol-lowering medications. Monitor geriatric patients receiving atorvastatin for increased risk of myopathy.
Use atorvastatin with caution in patients with a recent hemorrhagic stroke. Consider the risk versus benefit of atorvastatin 80 mg/day in patients with recent hemorrhagic stroke. In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg/day vs. placebo was administered in 4,731 subjects without coronary heart disease who had a stroke or transient ischemic attack (TIA) within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI 1.09 to 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (1.6%) as compared to the placebo group (0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.
Exacerbation and induction of myasthenia gravis has been reported during treatment with statins, including atorvastatin. 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.
-Atorvastatin 40 or 80 mg once daily is considered to be a high-intensity statin (expected to lower low-density lipoprotein cholesterol (LDL-C) by 50% or more), while atorvastatin 10 or 20 mg once daily is considered to be a moderate-intensity statin (expected to lower LDL-C by 30% to 49%).
-Choice of high- or moderate-intensity statin therapy is dependent on patient age, baseline LDL-C, ASCVD risk factors, and concomitant diseases. High-intensity therapy provides greatest LDL-C reductions and is associated with a significantly greater reduction in ASCVD events vs. moderate-intensity therapy.
-Guidelines recommend assessment of liver function at baseline and if signs or symptoms of hepatic injury occur.
-Monitor lipid concentrations at 4 to 12 weeks after initiation or dose adjustment, and then every 3 to 12 months as necessary.
NOTE: In pediatric patients (boys and postmenarchal girls 10 to 17 years of age), atorvastatin is FDA-approved for the treatment of heterozygous familial high cholesterol and is recommended for hyperlipidemia when either: 1) the LDL remains 190 mg/dL or more, or 2) the LDL remains 160 mg/dL or more and there is an increased risk for cardiovascular disease (e.g., positive family history of premature cardiovascular disease or two or more other risk factors are present).
For general dosing information in persons requiring high-intensity statin therapy :
Oral dosage:
Adults: 80 mg PO once daily. May decrease dose to 40 mg PO once daily if unable to tolerate the higher dose.
For general dosing information in persons requiring moderate-intensity statin therapy:
Oral dosage:
Adults: 10 or 20 mg PO once daily.
For the treatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control, for the purpose of reducing the risk of cardiovascular events (e.g., myocardial infarction prophylaxis, stroke prophylaxis):
Oral dosage:
Adults: 10 to 20 mg PO once daily initially. May start at 40 mg PO once daily in patients requiring greater than 45% LDL-reduction. The dosage range is 10 to 80 mg PO once daily (mean LDL reduction range: 43% to 60% LDL). The daily dose may be given at any time during the day. After atorvastatin initiation, assess LDL-C levels as early as 4 weeks or when clinically appropriate and adjust dosage as necessary. In general, geriatric patients may have an increased cholesterol-lowering response to HMG-CoA reductase inhibitors. Coadministration of certain drugs with atorvastatin may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 10 years and older (females should be at least 1 year post-menarche): 10 mg PO once daily initially. The dosage range is 10 to 20 mg PO once daily. The daily dose may be given at any time during the day. After atorvastatin initiation, assess LDL-C levels as early as 4 weeks or when clinically appropriate and adjust dosage as necessary. In a randomized, placebo-controlled trial of pediatric patients with familial hypercholesterolemia or severe hyperlipidemia (n = 187), mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 32%, 40%, and 12%, respectively, after 26 weeks of treatment with atorvastatin. Coadministration of certain drugs with atorvastatin may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 6 to 9 years*: 5 mg PO once daily increased to 10 mg PO once daily after four weeks if the goal LDL of less than 130 mg/dL was not reached was used in a small, short-term study of pediatric patients with heterozygous familial hypercholesterolemia. Patients were dosed based on Tanner Stage, with Tanner Stage 1 patients (n = 15, age 6 to 14 years) receiving an initial dose of 5 mg/day PO and Tanner Stage 2 patients (n = 24, age 9 to 17 years) receiving an initial dose of 10 mg/day PO. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 34%, 40.7%, and 6%, respectively, in the Tanner Stage 1 patients after eight weeks of treatment. Similar reductions were seen in the Tanner Stage 2 patients, with the exception of triglycerides, which decreased by 21%. Although pharmacologic therapy is not generally recommended for patients less than ten years of age or Tanner Stage 1, it may be considered in patients with severe primary hyperlipidemia or high level risk factors (e.g. diabetes, organ transplant, obesity, hypertension, chronic renal disease, strong family history of premature cardiovascular disease). Coadministration of certain drugs with atorvastatin may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the reduction of cardiovascular mortality and events and reduction of heart failure hospitalizations in person with clinically evident coronary heart disease:
Oral dosage:
Adults: 80 mg PO once daily; reduce dose to 40 mg PO once daily if unable to tolerate higher dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In persons with clinical atherosclerotic coronary vascular disease (ASCVD), reduction in LDL-C should be targeted with high-intensity or maximally-tolerated statin dosing unless contraindicated. High-intensity dosing aims to reduce LDL-C by 50% or more.
For slowing the progression of atherosclerosis* (e.g., carotid, coronary, femoral):
Oral dosage:
Adults: 80 mg PO once daily has been shown to reduce the progression of atherosclerosis in clinical trials. Coadministration of certain drugs with atorvastatin may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For cerebral vasospasm prophylaxis* after aneurysmal subarachnoid hemorrhage:
Oral dosage:
Adults: Dosage not established. 40 mg PO once daily for 21 days has been used. Coadministration of certain drugs with atorvastatin may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of chronic heart failure*:
Oral dosage:
Adults: Dosage not established. 10 to 40 mg PO daily for 6 to 12 months has been studied. Limited data suggest atorvastatin may improve inflammatory markers and left ventricular ejection fraction, especially in patients with dilated cardiomyopathy. However, clinical practice guidelines for the treatment of heart failure in adults recommend statins only in patients with a recent or remote history of myocardial infarction or acute coronary syndrome to prevent symptomatic heart failure and cardiovascular events. Coadministration of certain drugs with atorvastatin may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For graft coronary artery disease prevention after heart transplantation*:
Oral dosage:
Children and Adolescents: 0.2 mg/kg/day PO rounded to the nearest 2.5 mg resulted in a lower incidence of graft coronary artery disease (GCAD) compared to no early (before 9 weeks post-transplant) HMG-coenzyme A reductase inhibitor therapy. Atorvastatin initiated before the ninth week post-transplant (n = 33, mean age 12.3 +/- 3.7 years) was compared to a control group who did not receive the drug before the ninth week (n = 32, mean age 10.4 +/- 6.1 years). Patients in the control group started atorvastatin at an average of 95 weeks post-transplant. Significantly fewer patients in the early atorvastatin group developed graft coronary artery disease compared to the control group (2 vs. 12, p less than 0.005). Freedom from graft coronary artery disease at 1, 3, and 5 years was significantly higher in those patients receiving early atorvastatin treatment (97%, 93%, and 93%, respectively) compared to the control group (72%, 65%, and 60%, respectively). In addition, patients in the early atorvastatin group had fewer episodes of treated rejection in the first year post-transplant compared to the control group (0.2 +/- 0.4 episodes vs. 1 +/- 1.1 episodes, respectively [p = 0.05 or less]).
Maximum Dosage Limits:
-Adults
80 mg/day PO.
-Geriatric
80 mg/day PO.
-Adolescents
20 mg/day PO.
-Children
10 to 12 years: 20 mg/day PO.
6 to 9 years: Safety and efficacy have not been established; however, doses up to 10 mg/day PO have been included in some study protocols.
1 to 5 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin.
Patients with Renal Impairment Dosing
Renal impairment has no influence on atorvastatin plasma concentrations or LDL cholesterol reductions. No dosage adjustments are needed.
Intermittent hemodialysis
Hemodialysis does not enhance the clearance of atorvastatin or its metabolites ; no dosage adjustment is needed.
*non-FDA-approved indication
Abrocitinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with abrocitinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; abrocitinib is a P-gp inhibitor.
Adagrasib: (Major) Coadministration of atorvastatin with adagrasib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Aliskiren: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
Alogliptin; Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Amiodarone: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with amiodarone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; amiodarone is a P-gp inhibitor.
Amobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Apalutamide: (Moderate) Monitor for decreased efficacy of atorvastatin if coadministration with apalutamide is necessary. Atorvastatin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80% if the doses were separated, but increased the exposure of atorvastatin by 30% with simultaneous administration.
Aprepitant, Fosaprepitant: (Moderate) Use caution if atorvastatin and a multi-day regimen of oral aprepitant are used concurrently; monitor for an increase in atorvastatin-related adverse effects for several days after administration. Atorvastatin 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 atorvastatin. 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.
Aspirin, ASA; Butalbital; Caffeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
Atazanavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and atazanavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor.
Atazanavir; Cobicistat: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and atazanavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Berotralstat: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with berotralstat is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; berotralstat is a P-gp 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.
Brigatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with brigatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
Butabarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Acetaminophen: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Acetaminophen; Caffeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Cannabidiol: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with cannabidiol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with capmatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and a substrate of the efflux transporter BCRP. Capmatinib is a P-gp and BCRP inhibitor. If coadministration is unavoidable, consider a decrease in the atorvastatin dosage in accordance with the approved atorvastatin prescribing information and clinical goals for the patient.
Carbamazepine: (Moderate) Carbamazepine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates, such as atorvastatin.
Carvedilol: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.
Ceritinib: (Major) Consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness) if coadministration of atorvastatin with ceritinib is required, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ceritinib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration of ceritinib with atorvastatin may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin.
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) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking ciprofloxacin. Coadministration of ciprofloxacin, a moderate CYP3A4 inhibitor, with atorvastatin, a CYP3A4 substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses.
Clarithromycin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Cobicistat: (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
Colestipol: (Moderate) Coadministration of atorvastatin with colestipol resulted in approximately 25% lower plasma concentrations of atorvastatin. However, LDL-cholesterol reduction was greater when atorvastatin and colestipol were administered together than when either drug was given alone.
Conivaptan: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; conivaptan is a P-gp inhibitor.
Conjugated Estrogens; Bazedoxifene: (Minor) In clinical evaluation, atorvastatin 20 mg was given once with bazedoxifene 40 mg in 30 postmenopausal women. Co-administration decreased the Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%. The clinical effect of this change is not known. Monitor patients for loss of efficacy and increased side effects during conjugated estrogens; bazedoxifene therapy. In addition, bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration decreased the Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively. The possibility of reduced anti-lipemic efficacy should be considered; however, the clinical relevance of this interaction has not been determined, since the AUC (exposure) of atorvastatin remained unchanged.
Cyclosporine: (Major) FDA-approved labeling recommends avoiding coadministration of atorvastatin and cyclosporine. However, guidelines recommend limiting the atorvastatin dose to 10 mg/day in patients receiving cyclosporine. Concomitant administration increases the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higher atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone.
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.
Dalfopristin; Quinupristin: (Moderate) Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
Danazol: (Moderate) The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with atorvastatin. Danazol is a CYP3A4 inhibitor and may inhibit the metabolism of atorvastatin, a CYP3A4 substrate. Until more data are available, danazol should be used very cautiously, if at all, in patients receiving statins which are CYP3A4 substrates.
Daptomycin: (Major) Temporarily suspend HMG-CoA reductase inhibitors in patients taking daptomycin as cases of rhabdomyolysis have been reported with concomitant use. Both agents can cause myopathy and rhabdomyolysis when given alone and the risk may be increased when given together.
Darolutamide: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; darolutamide is a BCRP and OATP1B1/3 inhibitor.
Darunavir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Darunavir; Cobicistat: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Delavirdine: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when delavirdine is given in combination with HMG-CoA reductase inhibitors. Coadminister delavirdine and atorvastatin cautiously; use the lowest possible dose of atorvastatin. Delavirdine is a potent inhibitor of CYP3A4. Atorvastatin is a substrate of CYP3A4. If these drugs are coadministered, carefully monitor the patient. 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.
Desogestrel; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Digoxin: (Major) Measure serum digoxin concentrations before initiating atorvastatin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Coadministration of digoxin and atorvastatin increases the serum concentration and AUC of digoxin by 22% and 15%, respectively. Digoxin and atorvastatin are both substrates for P-glycoprotein (P-gp).
Diltiazem: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with diltiazem is necessary. Atorvastatin is a CYP3A substrate; diltiazem is a CYP3A inhibitor. Concomitant use has been shown to increase atorvastatin overall exposure by 1.5-fold.
Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A, CYP2D6, and P-gp. Atorvastatin is a substrate for CYP3A4 and P-gp. Monitor for signs and symptoms of myopathy in patients receiving dronedarone concurrently with atorvastatin.
Drospirenone; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Efavirenz: (Moderate) Efavirenz has the 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 atorvastatin with caution.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz has the 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 atorvastatin with caution.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz has the 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 atorvastatin with caution.
Elacestrant: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elacestrant is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a substrate of BCRP and P-gp; elacestrant inhibits BCRP and P-gp.
Elbasvir; Grazoprevir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with grazoprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elexacaftor is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is an OATP1B1/3 substrate; elexacaftor is an OATP1B1/3 inhibitor.
Eliglustat: (Moderate) Coadministration of atorvastatin and eliglustat may result in increased plasma concentrations of atorvastatin. Monitor patients closely for atorvastatin-related adverse effects including myalgia, myopathy, myasthenia, and/or rhabdomyolysis; if appropriate, consider reducing the atorvastatin dosage and titrating to clinical effect. Atorvastatin is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
Eltrombopag: (Moderate) Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as atorvastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for adverse reactions if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Enasidenib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp, BCRP, and OATP1B1/3 substrate; enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor.
Encorafenib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a substrate of OATP1B1/3 and BCRP; encorafenib is an OATP1B1/3 and BCRP inhibitor.
Erythromycin: (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with erythromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a CYP3A and OATP1B1/3 substrate; erythromycin is a moderate CYP3A and OATP1B1/3 inhibitor.
Eslicarbazepine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atorvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atorvastatin if coadministered with eslicarbazepine. Adjust the dose of atorvastatin if clinically significant alterations in serum lipids are noted.
Ethinyl Estradiol; Norelgestromin: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Ethinyl Estradiol; Norgestrel: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Etonogestrel; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Etravirine: (Moderate) Concomitant use of etravirine and atorvastatin decreases atorvastatin serum concentrations and increases concentrations of the metabolite, 2-OH-atorvastatin. Atorvastatin may be a substrate of the CYP3A4 isoenzyme and etravirine induces the CYP3A4 isoenzyme. According to the manufacturer of etravirine, atorvastatin can be given without any dose adjustments, although its dose may need to be altered based on clinical response. The risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors.
Everolimus: (Moderate) Carefully weigh the benefits of combined use of everolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend maximum atorvastatin doses of 10 mg/day unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. In a drug interaction study in healthy subjects, the pharmacokinetics of atorvastatin were not significantly altered by single dose administration of everolimus.
Fenofibrate: (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with fenofibrate is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Fenofibric Acid: (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with fenofibric acid is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Fluconazole: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a CYP3A substrate; fluconazole is a CYP3A inhibitor.
Fosamprenavir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with fosamprenavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Fostemsavir: (Moderate) Use the lowest possible starting dose for atorvastatin when administered concurrently with fostemsavir and monitor for signs of atorvastatin-associated adverse events, such as rhabdomyolysis. Use of these drugs together may increase the systemic exposure of atorvastatin. Atorvastatin is a substrate for the transporters OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
Futibatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; futibatinib is a P-gp and BCRP inhibitor.
Gemfibrozil: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with gemfibrozil is necessary due to an increased risk of myopathy and rhabdomyolysis. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable if clinically indicated and fenofibrate or fenofibric acid is not an option. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Gilteritinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; gilteritinib is a P-gp and BCRP inhibitor.
Glecaprevir; Pibrentasvir: (Major) Avoid the concurrent use of atorvastatin and glecaprevir due to an increased risk of myopathy/rhabdomyolysis. Coadministration may increase the plasma concentrations of atorvastatin. Atorvastatin is a substrate of the drug transporters P-glycoprotein (P-gp) and OATP1B1/3; glecaprevir is an inhibitor of these transporters. In drug interaction studies, coadministration of atorvastatin with glecaprevir; pibrentasvir resulted in an approximately 8-fold increase in the AUC of atorvastatin. (Major) Avoid the concurrent use of atorvastatin and pibrentasvir due to an increased risk of myopathy/rhabdomyolysis. Coadministration may increase the plasma concentrations of atorvastatin. Atorvastatin is a substrate of the drug transporters P-glycoprotein (P-gp) and OATP1B1; pibrentasvir is an inhibitor of these transporters. In drug interaction studies, coadministration of atorvastatin with glecaprevir; pibrentasvir resulted in an approximately 8-fold increase in the AUC of atorvastatin.
Grapefruit juice: (Major) Avoid grapefruit juice quantities greater than 1.2 L daily in patients taking atorvastatin to avoid the potential for drug accumulation and toxicity (i.e., myopathy and rhabdomyolysis), Grapefruit juice contains a compound that inhibits the CYP3A4 isozyme in the gut wall. In one pharmacokinetic study, coadministration of 240 mL grapefruit juice once daily with a single 40 mg dose of atorvastatin resulted in a 37% increase in the AUC and a 16% increase in Cmax of atorvastatin. Excessive consumption of grapefruit juice (i.e., 750 mL to 1.2 L/day) has been reported to result in an up to 2.5-fold increase in AUC and/or a 71% increase in Cmax of atorvastatin.
Hydantoins: (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Idelalisib: (Major) Coadministration of idelalisib with atorvastatin may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Idelalisib is a strong CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Imatinib: (Major) The risk of developing myopathy during therapy with atorvastatin, a CYP3A4 substrate, is increased if coadministered with imatinib, STI-571, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and imatinib, STI-571 therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Indinavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with indinavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with CYP3A4 inhibitors such as indinavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and protease inhibitor therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Isavuconazonium: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with isavuconazonium is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Isavuconazole, the active moiety of isavuconazonium, inhibits the CYP3A4-mediated metabolism and P-glycoprotein (P-gp)-mediated transport of atorvastatin.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Coadministration of atorvastatin with rifampin may result in variable decreases in atorvastatin exposures, with the potential for reduced antilipemic efficacy. If concomitant use of these drugs is required, atorvastatin and rifampin should be simultaneously administered. Atorvastatin is a CYP3A4 and OATP1B1 substrate. Rifampin is a strong CYP3A4 inducer and OATP1B1 inhibitor. As a result of the dual interaction mechanisms, delayed administration of atorvastatin after rifampin administration has been associated with a significant reduction in atorvastatin plasma concentrations. To evaluate this interaction, monitor serum lipid concentrations during coadministration.
Isoniazid, INH; Rifampin: (Moderate) Coadministration of atorvastatin with rifampin may result in variable decreases in atorvastatin exposures, with the potential for reduced antilipemic efficacy. If concomitant use of these drugs is required, atorvastatin and rifampin should be simultaneously administered. Atorvastatin is a CYP3A4 and OATP1B1 substrate. Rifampin is a strong CYP3A4 inducer and OATP1B1 inhibitor. As a result of the dual interaction mechanisms, delayed administration of atorvastatin after rifampin administration has been associated with a significant reduction in atorvastatin plasma concentrations. To evaluate this interaction, monitor serum lipid concentrations during coadministration.
Istradefylline: (Moderate) Monitor for atorvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) if coadministration of istradefylline 40 mg daily is necessary as atorvastatin exposure may be increased. Atorvastatin is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak inhibitor of CYP3A4 and P-gp. Coadministration of atorvastatin and istradefylline 40 mg daily increased the atorvastatin exposure by 1.5-fold.
Itraconazole: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with itraconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Itraconazole inhibits the CYP3A4 metabolism of atorvastatin. Itraconazole increases the AUC of atorvastatin by 2.5 to 3.3-fold, which is substantially less than the effect of itraconazole on the AUC of simvastatin and lovastatin (increased 19-fold and 20-fold, respectively).
Ketoconazole: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with ketoconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Ketoconazole inhibits the CYP3A and P-gp-mediated metabolism of atorvastatin. In addition, HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis and should be used with caution when given concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
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 atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with lasmiditan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
Leflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Lenacapavir: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with lenacapavir is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; lenacapavir is a P-gp and BCRP inhibitor.
Leniolisib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with leniolisib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; leniolisib is an inhibitor of BCRP and OATP1B1/3.
Letermovir: (Major) Do not exceed an atorvastatin dosage of 20 mg daily and closely monitor for myopathy and rhabdomyolysis if coadministration with letermovir is necessary. Concurrent use is not recommended for patients who are also receiving cyclosporine, as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of atorvastatin may occur during concurrent administration with letermovir. Atorvastatin is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. Coadministration of letermovir increased the AUC and Cmax of atorvastatin by 3.29-fold and 2.17-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Levoketoconazole: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with ketoconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Ketoconazole inhibits the CYP3A and P-gp-mediated metabolism of atorvastatin. In addition, HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis and should be used with caution when given concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established.
Levonorgestrel; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Lomitapide: (Major) Concomitant use of lomitapide and atorvastatin may result in increased lomitapide concentrations. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Atorvastatin is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Lonafarnib: (Contraindicated) Coadministration of atorvastatin and lonafarnib is contraindicated according to the manufacturer of lonafarnib. The manufacturer of atorvastatin recommends that if concomitant use of these drugs is required, a lower starting and maintenance dose of atorvastatin should be considered; monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 and P-gp substrate and lonafarnib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Lopinavir; Ritonavir: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with lopinavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); lopinavir is an OATP1B1 inhibitor.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of atorvastatin; if used together, monitor serum lipid concentrations. Atorvastatin is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of atorvastatin through the CYP3A pathway may lead to decreased plasma concentrations of atorvastatin, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
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 atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with maribavir is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; maribavir is a P-gp and BCRP inhibitor.
Methohexital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Midostaurin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; midostaurin is a dual BCRP/OATP1B1 inhibitor.
Mifepristone: (Major) Coadministration of atorvastatin with mifepristone may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor.
Mitapivat: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with mitapivat is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; mitapivat is a P-gp inhibitor.
Mitotane: (Major) Use caution if mitotane and atorvastatin are used concomitantly, and monitor for decreased efficacy of atorvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and atorvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of atorvastatin.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment.
Nefazodone: (Major) Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. There have been reports of rhabdomyolysis and myopathy when nefazodone has been administered to patients receiving statins metabolized by CYP3A4. Consider alternative therapy. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone.
Nelfinavir: (Major) Do not exceed 40 mg/day of atorvastatin if coadministration with nelfinavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Neratinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; neratinib is a P-gp inhibitor.
Nevirapine: (Moderate) Monitor for reduced cholesterol-lowering efficacy of atorvastatin if coadministration with nevirapine is necessary; a dose adjustment may be needed. Concomitant use may decrease atorvastatin exposure. Atorvastatin 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 atorvastatin. 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 atorvastatin. Carefully weigh the potential benefits and risk of combined therapy. If coadministered, use the lowest atorvastatin dose necessary and closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Discontinue atorvastatin immediately if myopathy is diagnosed or suspected.
Nicardipine: (Moderate) Monitor for evidence of myopathy if nicardipine is coadministered with atorvastatin. Nicardipine is an inhibitor of CYP3A4 isoenzymes. Coadministration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including atorvastatin.
Nilotinib: (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Nirmatrelvir; Ritonavir: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. (Major) Consider temporary discontinuation of atorvastatin during treatment with ritonavir-boosted nirmatrelvir; if this is not feasible, consider an alternative COVID-19 therapy. Atorvastatin does not need to be held prior to or after completing ritonavir-boosted nirmatrelvir. Coadministration may increase atorvastatin exposure resulting in increased toxicity. Atorvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Norethindrone; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Norgestimate; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Omeprazole; Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
Oritavancin: (Moderate) Atorvastatin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of atorvastatin may be reduced if these drugs are administered concurrently.
Oteseconazole: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oteseconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP substrate; oteseconazole is a BCRP inhibitor.
Oxcarbazepine: (Moderate) Monitor for potential reduced cholesterol-lowering efficacy when oxcarbazepine is coadministered with atorvastatin. Oxcarbazepine, which is a CYP3A4 inducer, may decrease the efficacy of atorvastatin, a CYP3A4 substrate.
Pacritinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pacritinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pacritinib is a P-gp and BCRP inhibitor.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and atorvastatin, a CYP3A4 substrate, may cause an increase in systemic concentrations of atorvastatin. Use caution when administering these drugs concomitantly.
Pentobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with atorvastatin. 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: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Pioglitazone; Glimepiride: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Pioglitazone; Metformin: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Pirtobrutinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pirtobrutinib is a P-gp and BCRP inhibitor.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and atorvastatin is contraindicated due to the risk of myopathy, rhabdomyolysis, and acute renal failure. If treatment with posaconazole is unavoidable, a brief suspension of atorvastatin therapy can be considered. Coadministration of these drugs may result in elevated atorvastatin plasma concentrations, causing an increased risk for adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for atorvastatin metabolism.
Pretomanid: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pretomanid is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pretomanid is a P-gp and BCRP inhibitor.
Primidone: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Probenecid; Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
Propafenone: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Quinine: (Moderate) Patients receiving concomitant atorvastatin and quinine should be monitored closely for muscle pain or weakness. Lower starting doses of atorvastatin should be considered while patients are receiving quinine. Atorvastatin is a CYP3A4 substrate; therefore, quinine has the potential to inhibit the metabolism of atorvastatin leading to an increased potential of rhabdomyolysis.
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: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
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.
Ribociclib: (Major) If concomitant use of atorvastatin with ribociclib is necessary, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ribociclib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Ribociclib; Letrozole: (Major) If concomitant use of atorvastatin with ribociclib is necessary, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ribociclib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Rifampin: (Moderate) Coadministration of atorvastatin with rifampin may result in variable decreases in atorvastatin exposures, with the potential for reduced antilipemic efficacy. If concomitant use of these drugs is required, atorvastatin and rifampin should be simultaneously administered. Atorvastatin is a CYP3A4 and OATP1B1 substrate. Rifampin is a strong CYP3A4 inducer and OATP1B1 inhibitor. As a result of the dual interaction mechanisms, delayed administration of atorvastatin after rifampin administration has been associated with a significant reduction in atorvastatin plasma concentrations. To evaluate this interaction, monitor serum lipid concentrations during coadministration.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and atorvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Ritonavir: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
Saquinavir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with saquinavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Sarilumab: (Moderate) Utilize caution with concomitant use of sarilumab and CYP3A4 substrate drugs, such as atorvastatin, 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 exposure to another "statin" was noted in a drug interaction study. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Atorvastatin is a CYP3A4 substrate.
Secobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Selpercatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with selpercatinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin 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 atorvastatin, 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: (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment.
Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with taurursodiol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; taurursodiol is a P-gp and BCRP inhibitor.
Sofosbuvir; Velpatasvir: (Major) Monitor patients closely when atorvastatin is coadministered with velpatasvir as this may significantly increase the serum concentrations of atorvastatin, which may increase the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate of the P-glycoprotein (P-gp) and OATP1B1 transporters as well as CYP3A4, while velpatasvir inhibits P-gp, OATP1B1, and CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Monitor patients closely when atorvastatin is coadministered with velpatasvir as this may significantly increase the serum concentrations of atorvastatin, which may increase the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate of the P-glycoprotein (P-gp) and OATP1B1 transporters as well as CYP3A4, while velpatasvir inhibits P-gp, OATP1B1, and CYP3A4. (Moderate) Caution is advised when administering voxilaprevir with atorvastatin. Taking these drugs together may increase atorvastatin plasma concentrations; thereby increasing the risk for adverse events, such as myopathy or rhabdomyolysis. Initiate atorvastatin at the lowest approved dose. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Atorvastatin is a substrate of P-glycoprotein (P-gp) and Organic Anion Transporting Polypeptides 1B1 (OATP1B1). Voxilaprevir is an inhibitor of both P-gp and OATP1B1.
Sorafenib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sorafenib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sotorasib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; sotorasib is a P-gp and BCRP inhibitor.
Sparsentan: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sparsentan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; sparsentan is a P-gp and BCRP inhibitor.
Spironolactone: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
Spironolactone; Hydrochlorothiazide, HCTZ: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Coadministration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including atorvastatin.
Streptogramins: (Moderate) Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
Tacrolimus: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and atorvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. Atorvastatin doses above 10 mg/day are not recommended without close monitoring of creatinine kinase and symptoms of muscle-related toxicity.
Temsirolimus: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions if coadministration with temsirolimus is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of atorvastatin.
Tepotinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with tepotinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin 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.
Tipranavir: (Major) Avoid the concurrent use of atorvastatin and tipranavir used in combination with ritonavir due to the increased risk of developing myopathy/rhabdomyolysis. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Tocilizumab: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as atorvastatin, 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 the exposure of another "statin" 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. Atorvastatin is a CYP3A4 substrate.
Trandolapril; Verapamil: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking verapamil. Coadministration of verapamil, a P-gp inhibitor, with atorvastatin, a P-gp substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses.
Trofinetide: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor.
Tucatinib: (Major) Coadministration of atorvastatin with tucatinib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Tucatinib is a strong CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and atorvastatin may result in altered concentrations of atorvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (P-gp) and an inducer of CYP3A4. Atorvastatin is a substrate of P-gp and CYP3A4 and an inhibitor of P-gp. Use caution and monitor patients for toxicity and efficacy.
Verapamil: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking verapamil. Coadministration of verapamil, a P-gp inhibitor, with atorvastatin, a P-gp substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses.
Voclosporin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voclosporin is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and OATP1B1 substrate; voclosporin is a P-gp and OATP1B1 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Voriconazole: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with voriconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Voriconazole inhibits the CYP3A4-mediated metabolism of atorvastatin.
Warfarin: (Moderate) Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, 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.
Zonisamide: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with zonisamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; zonisamide is a P-gp inhibitor.
Atorvastatin is a selective, competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol levels in hepatic cells. This, in turn, results in upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation. Atorvastatin ultimately reduces the levels of circulating total cholesterol, LDL-cholesterol, and serum triglycerides. Drug dosage rather than systemic drug concentration correlates better with LDL-cholesterol reduction. As with other HMG-CoA reductase inhibitors, atorvastatin exhibits no effects on antipyrine hepatic metabolism.
HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.
Atorvastatin is administered orally. It is 98% or more bound to plasma proteins. A blood/plasma ratio of 0.25 indicates poor drug penetration into red blood cells. Atorvastatin undergoes extensive metabolism to active ortho- and para-hydroxylated metabolites which account for approximately 70% of the circulating HMG-CoA reductase inhibitory activity. Elimination of atorvastatin and its metabolites occurs primarily in bile following hepatic and/or extrahepatic metabolism. It does not appear to undergo enterohepatic recirculation. Less than 2% of an oral dose is recovered in the urine. The mean plasma elimination half-life is approximately 14 hours, however, the half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours because of the active metabolites.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), OATP1B1, OATP1B3, BCRP
Atorvastatin is a substrate of CYP3A4 hepatic metabolism. Atorvastatin is also a substrate of P-gp and an inhibitor of P-gp. Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Atorvastatin has the potential for significant drug interactions with CYP3A4 inhibitors, which may result in increased HMG-CoA reductase inhibition and potential toxicity (i.e., myopathy, rhabdomyolysis). Inducers of CYP3A4 can reduce atorvastatin plasma concentrations.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, atorvastatin is rapidly absorbed with peak plasma concentrations occurring within 1 to 2 hours. The extent of absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. Presystemic clearance and/or hepatic first-pass metabolism accounts for the low systemic bioavailability. Food decreases the rate and extent of atorvastatin absorption by approximately 25% and 9%, respectively, however, LDL-cholesterol reduction is similar whether the drug is given with or without food. Similarly, atorvastatin plasma concentrations are lower following evening doses compared with morning dosing and LDL-cholesterol reduction is the same regardless of the time of day the drug is administered. Administration of atorvastatin liquid with a high fat meal resulted in a 30% decrease in atorvastatin AUC and a 63% decrease in Cmax compared to administration without food. The decrease in atorvastatin exposure can be clinically significant; therefore atorvastatin liquid should be taken on an empty stomach (1 hour before or 2 hours after a meal).
-Special Populations
Hepatic Impairment
In patients with chronic alcoholic hepatic disease, atorvastatin plasma concentrations are increased. Cmax and AUC are both 4-fold greater in patients with Child-Pugh Class A hepatic disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh Class B hepatic disease. Acute liver disease and decompensated cirrhosis are contraindications to the use of atorvastatin.
Renal Impairment
Renal disease has no influence on atorvastatin plasma concentrations or LDL cholesterol reductions; no dosage adjustments are needed. Hemodialysis does not enhance the clearance of atorvastatin or its metabolites.
Pediatrics
Children and Adolescents
Based on the results of a population pharmacokinetic study (n = 39), the oral clearance of atorvastatin in pediatric patients 6 to 17 years of age is similar to that reported in adult patients. The estimated oral clearance in Tanner Stage 1 (approximately 35 kg) and Tanner Stage 2 (approximately 50 kg) patients was 533 L/hour and 543 L/hour, respectively, compared to an estimated clearance of 699 L/hour in adults. Weight was the primary factor affecting the variability of atorvastatin pharmacokinetics in pediatric patients.
Geriatric
Plasma concentrations of atorvastatin are higher (about 40% for Cmax and 30% for AUC) in healthy elderly subjects (65 years old or more) than in young adults.
Gender Differences
Plasma concentrations of atorvastatin differ for women compared to concentrations in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there are no clinically significant differences in LDL reduction.
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