CADUET (amlodipine and atorvastatin) tablets combine the calcium channel blocker amlodipine besylate with the HMG-CoA-reductase inhibitor atorvastatin calcium. Amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S. Atorvastatin calcium is chemically described as [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. Its empirical formula is (C 33 H 34 FN 2 O 5 ) 2 Ca•3H 2 O. The structural formulae for amlodipine besylate and atorvastatin calcium are shown below. Amlodipine besylate Atorvastatin calcium CADUET contains amlodipine besylate, a white to off-white crystalline powder, and atorvastatin calcium, also a white to off-white crystalline powder. Amlodipine besylate has a molecular weight of 567.1 and atorvastatin calcium has a molecular weight of 1209.42. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Atorvastatin calcium is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol. CADUET is available as film-coated tablets containing: • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 10 mg atorvastatin equivalent to 10.4 mg atorvastatin calcium. • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 20 mg atorvastatin equivalent to 20.7 mg atorvastatin calcium. • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 40 mg atorvastatin equivalent to 41.4 mg atorvastatin calcium. • 5 mg amlodipine equivalent to 6.9 mg amlodipine besylate and 80 mg atorvastatin equivalent to 82.9 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 10 mg atorvastatin equivalent to 10.4 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 20 mg atorvastatin equivalent to 20.7 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 40 mg atorvastatin equivalent to 41.4 mg atorvastatin calcium. • 10 mg amlodipine equivalent to 13.9 mg amlodipine besylate and 80 mg atorvastatin equivalent to 82.9 mg atorvastatin calcium. Each film-coated tablet also contains calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon dioxide (anhydrous), magnesium stearate, Opadry ® II White 85F28751 (polyvinyl alcohol, titanium dioxide, PEG 3000, and talc) or Opadry ® II Blue 85F10919 (polyvinyl alcohol, titanium dioxide, PEG 3000, talc, and FD&C blue #2). Chemical Structure Chemical Structure

CADUET (amlodipine and atorvastatin) is indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate. CADUET is a combination of amlodipine besylate, a calcium channel blocker, and atorvastatin calcium, a HMG-CoA-reductase inhibitor (statin), indicated in patients for whom treatment with both amlodipine and atorvastatin is appropriate. Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Amlodipine is indicated for the treatment of Coronary Artery Disease. Atorvastatin is indicated: • To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. • As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. • As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia. Amlodipine Hypertension Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Amlodipine may be used alone or in combination with other antihypertensive agents. Coronary Artery Disease (CAD) Chronic Stable Angina Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal agents. Vasospastic Angina (Prinzmetal’s or Variant Angina) Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy or in combination with other antianginal agents. Angiographically Documented CAD In patients with recently documented CAD by angiography and without heart failure or an ejection fraction < 40%, amlodipine is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure. Atorvastatin Atorvastatin is indicated: • To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD • As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). • As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia o Hypertriglyceridemia

CADUET tablets are formulated for oral administration in the following strength combinations of amlodipine / atorvastatin: 5 mg/10 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “051”. 5 mg/20 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “052”. 5 mg/40 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “054”. 5 mg/80 mg tablets: White, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “058”. 10 mg/10 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “101”. 10 mg/20 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “102”. 10 mg/40 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “104”. 10 mg/80 mg tablets: Blue, oval, film-coated tablets debossed, blank on one side and with product code on the other side: “CDT” and “108”. Tablets contain amlodipine besylate equivalent to amlodipine 5 or 10 mg and atorvastatin calcium equivalent to atorvastatin 10, 20, 40, or 80 mg.

Usual starting dose (mg daily) Maximum dose (mg daily) Amlodipine 5 Start small adults or children, fragile, or elderly patients, or patients with hepatic insufficiency on 2.5 mg once daily. 10 Atorvastatin 10–20 Start patients requiring large LDL-C reduction (> 45%) at 40 mg once daily. 80 CADUET Dosage of CADUET must be individualized on the basis of both effectiveness and tolerance for each individual component in the treatment of hypertension/angina and hyperlipidemia. Select doses of amlodipine and atorvastatin independently. CADUET may be substituted for its individually titrated components. Patients may be given the equivalent dose of CADUET or a dose of CADUET with increased amounts of amlodipine, atorvastatin, or both for additional antianginal effects, blood pressure lowering, or lipid-lowering effect. CADUET may be used to provide additional therapy for patients already on one of its components. CADUET may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. Important Dosage Information Take CADUET orally once daily at any time of the day, with or without food. Amlodipine The usual initial antihypertensive oral dosage of amlodipine is 5 mg once daily, and the maximum dose is 10 mg once daily. Pediatric (age > 6 years), small adult, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy. Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently. Angina The recommended dosage of amlodipine for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect. Coronary Artery Disease The recommended dosage range of amlodipine for patients with CAD is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg . Pediatrics The effective antihypertensive oral dose of amlodipine in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients . Atorvastatin Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin, and adjust the ‎dosage if ‎‎necessary.‎ ‎ Recommended Dosage in Adult Patients The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. Recommended Dosage in Pediatric Patients 10 Years of Age and Older with H e FH The recommended starting dosage of atorvastatin is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH The recommended starting dosage of atorvastatin is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Dosage Modifications Due to Drug Interactions Concomitant use of atorvastatin with the following drugs requires dosage modification of atorvastatin . Anti-Viral Medications • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg once daily. • In patients taking nelfinavir, do not exceed atorvastatin 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics • In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg once daily. For additional recommendations regarding concomitant use of atorvastatin with other anti-viral medications, azole antifungals or macrolide antibiotics, .

• Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher CADUET dosage. Discontinue CADUET if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue CADUET in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing CADUET dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 2 , 5.1 , 7.3 , 8.5 , 8.6 ). • Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue CADUET if IMNM is suspected. • Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue CADUET. • Angina or myocardial infarction may occur with initiation or dose increase. • Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. However, acute hypotension is unlikely

Myopathy and Rhabdomyolysis CADUET may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including CADUET. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher CADUET dosage . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis CADUET exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., 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. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir or glecaprevir plus pibrentasvir with CADUET is not recommended. CADUET dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses (> 1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir . Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis . Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking CADUET . Discontinue CADUET if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if CADUET is discontinued. Temporarily discontinue CADUET 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, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the CADUET dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever

Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue CADUET if IMNM is suspected

Hepatic Dysfunction Increases in serum transaminases have been reported with use of atorvastatin . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury . Consider liver enzyme testing before atorvastatin initiation and when clinically indicated thereafter. Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin

Increased Angina and Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease

Hypotension Symptomatic hypotension is possible with use of amlodipine, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely

Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices

Increased Risk of Hemorrhagic Stroke in Patients on Atorvastatin 80 mg with Recent Hemorrhagic Stroke In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or Transient Ischemic Attack (TIA) within the preceding 6 months, were treated with atorvastatin 80 mg, 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, 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 non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 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 . Consider the risk/benefit of use of atorvastatin 80 mg in patients with recent hemorrhagic stroke.

Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the C max : 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine, which is not clinically meaningful. No drug interaction studies have been conducted with CADUET and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: • See full prescribing information for details regarding concomitant use of CADUET with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. • Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin. • Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive. • Digoxin: May increase digoxin plasma levels; monitor patients appropriately. Amlodipine 7.1 Impact of Other Drugs on Amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment . CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with amlodipine

Impact of Amlodipine on Other Drugs Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate . Atorvastatin 7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them . Table 3. Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 . Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) . Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention: • Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. • In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir do not exceed atorvastatin 20 mg. • In patients taking nelfinavir, do not exceed atorvastatin 40 mg . • Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. • Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters . Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg . Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin ( > 1 gram/day niacin) with atorvastatin. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin

Drug Interactions that may Decrease Exposure to Atorvastatin Table 4 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them. Table 4. Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin and rifampin simultaneously

Atorvastatin Effects on Other Drugs Table 5 presents atorvastatin's effect on other drugs and instructions for preventing or managing them. Table 5. Atorvastatin Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol . Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin. Digoxin Clinical Impact: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased . Intervention: Monitor patients taking digoxin appropriately.