rosuvastatin calcium 40 MG Oral Tablet [Crestor]

INDICATIONS AND USAGE Rosuvastatin tablets are an HMG Co-A reductase inhibitor indicated for: • adult patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDLC ( 1.1 ) • pediatric patients 8 to 17 years of age with heterozygous familial hypercholesterotemia (HeFH] to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy ( 1.2 ) • adult patients with hypertriglyceridemia as an adjunct to diet ( 1.3 ) • adult patients with primary dysbetalipoproteinemia [Type III hyperlipoproteinemia) as an adjunct to diet ( 1.4 ) • adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LOL-G, total-G, and ApoB ( 1.5 ) • slowing the progression of atherosclerosis as part of a treatment strategy lo lower total-C and LDL-C as an adjunct to diet ( 1.6 ) • risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors ( 1.7 ) Limitations of use ( 1.8 ): Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias. 1.1 Hyperlipidemia and Mixed Dyslipidemia Rosuvastatin tablets are indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C, ApoB, nonHDL-C, and triglycerides and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate. 1.2 Pediatric Patients with Familial Hypercholesterolemia Rosuvastatin tablets are indicated as an adjunct to diet to: • reduce Total-C, LDL-C and ApoB levels in children and adolescents 8 to 17 years of age with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C >190 mg/dL, or >160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors. Pediatric use information for patients 7 to 17 years of age with homozygous familial hypercholesterolemia (HoFH) is approved by AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.3 Hypertriglyceridemia Rosuvastatin tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. 1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia). 1.5 Adult Patients with Homozygous Familial Hypercholesterolemia Rosuvastatin tablets are indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia. 1.6 Slowing of the Progression of Atherosclerosis Rosuvastatin tablets are indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels. 1.7 Primary Prevention of Cardiovascular Disease In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥50 years old in men and >60 years old in women, hsCRP >2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease, rosuvastatin tablets are indicated to: • reduce the risk of stroke • reduce the risk of myocardial infarction • reduce the risk of arterial revascularization procedures 1.8 Limitations of Use Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.

DOSAGE AND ADMINISTRATION Take orally with or without food, at any time of day. ( 2.1 ) Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating rosuvastatin tablets, and adjust dosage if necessary. ( 2.1 ) Adults : Recommended dosage range is 5 to 40 mg once daily. ( 2.1 ) Pediatric Patients with HeFH : Recommended dosage range is 5 to 10 mg once daily for patients aged 8 to less than 10 years of age, and 5 to 20 mg once daily for patients aged 10 years and older. ( 2.2) Pediatric Patients with HoFH : Recommended dosage is 20 mg once daily for patients aged 7 years and older. ( 2.2 ) Asian Patients : Initiate at 5 mg once daily. Consider risks and benefits of treatment if not adequately controlled at doses up to 20 mg once daily. ( 2.4 ) Patients with Severe Renal Impairment (not on hemodialysis) : Initiate at 5 mg once daily; do not exceed 10 mg once daily. ( 2.5 ) See full prescribing information for rosuvastatin tablets dosage and administration modifications due to drug interactions. ( 2.6 ) 2.1 General Dosage and Administration Information Administer rosuvastatin tablets orally as a single dose at any time of day, with or without food. Swallow the tablets whole. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating rosuvastatin tablets, and adjust the dosage if necessary. If a dose is missed, advise patients not take an extra dose. Resume treatment with the next dose. When taking rosuvastatin tablets with an aluminum and magnesium hydroxide combination antacid, administer rosuvastatin tablets at least 2 hours before the antacid [ see Drug Interactions ( 7.2 ) ]. 2.2 Recommended Dosage in Adult Patients The dosage range for rosuvastatin tablets is 5 to 40 mg orally once daily. The recommended dose of rosuvastatin tablets depends on a patient's indication for usage, LDL-C, and individual risk for CV events. 2.3 Recommended Dosage in Pediatric Patients Dosage in Pediatric Patients 8 Years of Age and Older with HeFH The recommended dosage range is 5 mg to 10 mg orally once daily in patients aged 8 years to less than 10 years and 5 mg to 20 mg orally once daily in patients aged 10 years and older. Dosage in Pediatric Patients 7 Years of Age and Older with HoFH The recommended dosage is 20 mg orally once daily. 2.4 Dosing in Asian Patients Initiate rosuvastatin tablets at 5 mg once daily due to increased rosuvastatin plasma concentrations. Consider the risks and benefits of rosuvastatin tablets when treating Asian patients not adequately controlled at doses up to 20 mg once daily [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.8 ), and Clinical Pharmacology ( 12.3 )]. 2.5 Recommended Dosage in Patients with Renal Impairment In patients with severe renal impairment (CL cr less than 30 mL/min/1.73 m 2 ) not on hemodialysis, the recommended starting dosage is 5 mg once daily and should not exceed 10 mg once daily [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 )]. There are no dosage adjustment recommendations for patients with mild and moderate renal impairment. 2.6 Dosage Modifications Due to Drug Interactions Rosuvastatin Tablets Dosage Modifications Due to Drug Interactions Table 1 displays dosage modifications for rosuvastatin tablets due to drug interactions [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. Table 1: Rosuvastatin Tablets Dosage Modifications Due to Drug Interactions Concomitantly Used Drug Rosuvastatin Tablets Dosage Modifications Cyclosporine Do not exceed 5 mg once daily. Teriflunomide Do not exceed 10 mg once daily. Enasidenib Do not exceed 10 mg once daily. Capmatinib Do not exceed 10 mg once daily. Fostamatinib Do not exceed 20 mg once daily. Febuxostat Do not exceed 20 mg once daily. Gemfibrozil Avoid concomitant use. If used concomitantly, initiate at 5 mg once daily and do not exceed 10 mg once daily. Tafamidis Avoid concomitant use. If used concomitantly, initiate at 5 mg once daily and do not exceed 20 mg once daily. Antiviral Medications Sofbuvir/velpatasvir/voxilaprevir Ledipasvir/sofosbuvir Concomitant use not recommended. o Simeprevir o Dasabuvir/ombitasvir/paritaprevir/ritonavir o Elbasvir/Grazoprevir o Sofosbuvir/Velpatasvir o Glecaprevir/Pibrentasvir o Atazanavir/Ritonavir o Lopinavir/Ritonavir Initiate at 5 mg once daily. Do not exceed 10 mg once daily. Darolutamide Do not exceed 5 mg once daily. Regorafenib Do not exceed 10 mg once daily. Rosuvastatin Tablets Administration Modifications Due to Drug Interactions When taking rosuvastatin tablets with an aluminum and magnesium hydroxide combination antacid, administer rosuvastatin tablets at least 2 hours before the antacid [see Drug Interactions ( 7.2 )] .

WARNINGS AND PRECAUTIONS • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, darolutamide, regorafenib, certain anti-viral medicines or their combinations. Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue rosuvastatin tablets if signs or symptoms appear. ( 5.1 , 7.4 , 7.5 , 7.7 , 7.8 ) • Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. (5.2) • Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Perform liver enzyme tests before initiating therapy and as clinically indicated thereafter. (5.3) 5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg). Rosuvastatin tablets should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). Rosuvastatin tablets should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir) [ see Dosage and Administration (2) and Drug Interactions (7 )]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin tablets with colchicine [see Drug Interactions (7.9) ]. Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).Rosuvastatin therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin tablets. All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin tablets. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist 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. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM. 5.3 Liver Enzyme Abnormalities It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin tablets, and if signs or symptoms of liver injury occur. Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin tablets. Rosuvastatin tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [ see Clinical Pharmacology (12.3)]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin [ see Contraindications (4) ]. 5.4 Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs [ see Drug Interactions (7.6) ]. 5.5 Proteinuria and Hematuria In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscop

CONTRAINDICATIONS Rosuvastatin tablets is contraindicated in the following conditions: • Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus,urticaria, and angioedema have been reported with rosuvastatin tablets [ see Adverse Reactions (6.1) ]. • Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [ see Warnings and Precautions ( 5.3 ) ]. • Pregnancy [see Use in Specific Populations (8.1, 8.3 )] • Lactation. Limited data indicate that rosuvastatin tablets is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin tablets treatment should not breastfeed their infants [see Use in Specific Populations (8.2) ]. • Known hypersensitivity to product components ( 4 ) • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4 ) • Pregnancy ( 4 , 8.1 , 8.3) • Lactation ( 4 , 8.2)

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rosuvastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. 12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of rosuvastatin tablets are usually achieved by 4 weeks and is maintained after that. 12.3 Pharmacokinetics Absorption In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both C max and AUC increased in approximate proportion to rosuvastatin tablet dose. The absolute bioavailability of rosuvastatin is approximately 20%. The AUC of rosuvastatin does not differ following evening or morning drug administration. Effect of food Administration of rosuvastatin tablets with food did not affect the AUC of rosuvastatin. Distribution Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations. Elimination Metabolism Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound. Excretion Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. The elimination half-life of rosuvastatin is approximately 19 hours. Specific Populations Geriatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years). Pediatric Patients In a population pharmacokinetic analysis of two pediatric trials involving patients with HeFH 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients. Male and Female Patients There were no differences in plasma concentrations of rosuvastatin between males and females. Racial or Ethnic Groups A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among White, Hispanic, or Latino ethnicity, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a White control group. Patients with Renal Impairment Mild to moderate renal impairment (CL cr ≥30 mL/min/1.73 m 2 ) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CL cr <30 mL/min/1.73 m 2 ) not receiving hemodialysis compared with healthy subjects (CL cr >80 mL/min/1.73 m 2 ). Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function. Patients with Hepatic Impairment In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, C max and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function. Drug Interaction Studies Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of rosuvastatin tablets with medications that are inhibitors of these transporter proteins (e.g., cyclosporine, certain HIV protease inhibitors [see Dosage and Administration (2.6) and Drug Interactions (7.1) ] and ticagrelor [see Drug Interactions (7.1) ] ) may result in increased rosuvastatin plasma concentrations. Table 8: Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure QD= Once daily, BID= Twice daily, TID= Three times daily, QID= Four times daily 1 Single dose unless otherwise noted. 2 Clinically significant [ see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5 ) ] 3 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7 = 30% decrease, 11=11-fold increase in exposure) Coadministered drug and dosing regimen Rosuvastatin Mean Ratio (ratio with/without coadministered drug) No Effect = 1.0 Dose (mg) 1 Change in AUC Change in C max Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg) + Voxilaprevir (100 mg) once daily for 15 days 10mg, single dose 7.39 2 (6.68 to 8.18) 3 18.88 2 (16.23 to 21.96) 3 Cyclosporine – stable dose required (75 mg - 200 mg BID) 10 mg, QD for 10 days 7.1 2 11 2 Darolutamide 600 mg BID, 5 days 5mg, single dose 5.2 2 ~5 2 Regorafenib 160 mg QD, 14 days 5 mg, single dose 3.8 2 4.6 2 Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days 10 mg 3.1 2 7 2 Simeprevir 150 mg QD, 7 days 10 mg, single dose 2.8 2 (2.3 to 3.4) 3 3.2 2 (2.6 to 3.9) 3 Velpatasvir 100 mg once daily 10 mg, single dose 2.69 2 (2.46 to 2.94) 3 2.61 2 (2.32 to 2.92) 3 Ombitasvir 25mg/paritaprevir 150mg/ ritonavir 100mg + dasabuvir 400 mg BID 5mg, single dose 2.59 2 (2.09 to 3.21) 3 7.13 2 (5.11 to 9.96) 3 Teriflunomide Not available 2.51 2 2.65 2 Enasidenib 100 mg QD, 28 days 10 mg, single dose 2.44 3.66 Elbasvir 50 mg/grazoprevir 200mg once daily 10mg, single dose 2.26 2 (1.89 to 2.69) 3 5.49 2 (4.29 to 7.04) 3 Glecaprevir 400 mg/pibrentasvir 120mg once daily 5mg, once daily 2.15 2 (1.88 to 2.46) 3 5.62 2 (4.80-6.59) 3 Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days 20 mg, QD for 7 days 2.1 2 (1.7 to 2.6) 3 5 2 (3.4 to 6.4) 3 Capmatinib 400 mg BID 10 mg, single dose 2.08 2 (1.56 to 2.76) 3 3.04 2 (2.36 to 3.92) 3 Fostamatinib 100 mg BID 20 mg, single dose 1.96 2 (1.77 to 2.15) 3 1.88 2 (1.69 to 2.09) 3 Febuxostat 120 mg QD for 4 days 10 mg, single dose 1.9 2 (1.5 to 2.5) 3 2.1 2 (1.8 to 2.6) 3 Gemfibrozil 600 mg BID for 7 days 80 mg 1.9 2 (1.6 to 2.2) 3 2.2 2 (1.8 to 2.7) 3 Tafamidis 61 mg BID on Days 1 & 2, followed by QD on Days 3 to 9 10 mg 1.97 2 (1.68 to 2.31) 3 1.86 2 (1.59 to 2.16) 3 Eltrombopag 75 mg QD, 5 days 10 mg 1.6 (1.4 to 1.7) 3 2 (1.8 to 2.3) 3 Darunavir 600 mg/ritonavir 100 mg BID, 7 days 10 mg, QD for 7 days 1.5 (1.0 to 2.1) 3 2.4 (1.6 to 3.6) 3 Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days 10 mg 1.4 (1.2 to 1.6) 3 2.2 (1.8 to 2.7) 3 Dronedarone 400 mg BID 10 mg 1.4 Itraconazole 200 mg QD, 5 days 10 mg or 80 mg 1.4 (1.2 to 1.6) 3 1.3 (1.1 to 1.4) 3 1.4 (1.2 to 1.5) 3 1.2 (0.9 to 1.4) 3 Ezetimibe 10 mg QD, 14 days 10 mg, QD for 14 days 1.2 (0.9 to 1.6) 3 1.2 (0.8 to 1.6) 3 Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days 10 mg 1.1 1.5 Fenofibrate 67 mg TID for 7 days 10 mg ↔ 1.2 (1.1 to 1.3) 3 Rifampicin 450 mg QD, 7 days 20 mg ↔ Aluminum &