LYPQOZET

1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. LYPQOZET, which contains a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet to: reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. ( 1.1 ) reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments. ( 1.2 ) Limitations of Use No incremental benefit of LYPQOZET on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established. LYPQOZET has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. ( 1.3 ) 1.1 Primary Hyperlipidemia LYPQOZET is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. 1.2 Homozygous Familial Hypercholesterolemia (HoFH) LYPQOZET is indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e. g., LDL apheresis) or if such treatments are unavailable. 1.3 Limitations of Use No incremental benefit of LYPQOZET on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established. LYPQOZET has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis and myopathy [see Warnings and Precautions ( 5.1 )] Liver enzyme abnormalities [see Warnings and Precautions ( 5.3 )] Common adverse reactions (incidence ≥2% and greater than placebo) are: increased ALT, increased AST, and musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Althera at 1-877-495-3908 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Ezetimibe and Atorvastatin Tablets Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In an ezetimibe and atorvastatin tablets placebo-controlled clinical trial, 628 patients (age range 18 to 86 years, 59% women, 85% Caucasians, 6% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 12 weeks, 6% of patients on ezetimibe and atorvastatin tablets and 5% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group treated with ezetimibe and atorvastatin tablets that led to treatment discontinuation and occurred at a rate greater than placebo were: Myalgia (0.8%) Abdominal pain (0.8%) Increased hepatic enzymes (0.8%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in this trial were: increased ALT (5%), increased AST (4%), and musculoskeletal pain (4%). Ezetimibe and atorvastatin tablets have been evaluated for safety in 2403 patients in 7 clinical trials (one placebo-controlled trial and six active-controlled trials). Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with ezetimibe and atorvastatin tablets (n=255) and at an incidence greater than placebo, regardless of causality assessment, from the placebo-controlled trial. Table 2 * : Clinical and Selected Laboratory Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and Atorvastatin Tablets and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Placebo (%) n=60 Ezetimibe 10 mg (%) n=65 Atorvastatin † (%) n=248 Ezetimibe and Atorvastatin Tablets † (%) n=255 Nervous system disorders Dizziness 0 6 <1 2 Respiratory, thoracic, and mediastinal disorders Coughing 0 3 <1 2 Gastrointestinal disorders Abdominal pain 2 2 4 3 Nausea 0 2 5 3 Musculoskeletal and connective tissue disorders Arthralgia 0 5 6 3 Muscle weakness 0 2 0 2 Musculoskeletal pain 3 8 5 4 Metabolism and nutrition disorders Hyperkalemia 0 0 <1 2 Infections and infestations Bronchitis 0 2 2 2 Sinusitis 0 3 2 2 Vascular disorders Hot flushes 0 0 <1 2 Investigations ALT increased 0 0 2 5 AST increased 0 0 <1 4 * Placebo-controlled combination study in which the active ingredients equivalent to ezetimibe and atorvastatin tablets were coadministered. † All doses. After completing the 12-week study, eligible patients were assigned to coadministered ezetimibe and atorvastatin equivalent to ezetimibe and atorvastatin tablets (10/10 to 10/80) or atorvastatin (10 to 80 mg/day) for an additional 48 weeks. The long-term coadministration of ezetimibe plus atorvastatin had an overall safety profile similar to that of atorvastatin alone. Ezetimibe In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (age range 9 to 86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). Adverse reactions reported in ≥2% of patients treated with ezetimibe and at an incidence greater than placebo regardless of causality assessment are shown in Table 3. Table 3: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Ezetimibe 10 mg (%) n=2396 Placebo (%) n=1159 Gastrointestinal disorders Diarrhea 4.1 3.7 General disorders and administration site conditions Fatigue 2.4 1.5 Infections and infestations Influenza 2.0 1.5 Sinusitis 2.8 2.2 Upper respiratory tract infection 4.3 2.5 Musculoskeletal and connective tissue disorders Arthralgia 3.0 2.2 Pain in extremity 2.7 2.5 Atorvastatin In an atorvastatin placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%). Table 4 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥2% and at a rate greater than placebo in patients treated with atorvastatin (n=8755), from seventeen placebo-controlled trials. Table 4: Clinical Adverse Reactions Occurring in >2% in Patients Treated with any dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of patients). Adverse Reaction* Any Dose n=8755 Atorvastatin 10 mg n=3908 Atorvastatin 20 mg n=188 Atorvastatin 40 mg n=604 Atorvastatin 80 mg n=4055 Placebo n=7311 Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2 Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5 Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3 Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9 Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6 Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3 Nausea 4.0 3.7 3.7 7.1 3.8 3.5 Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6 Muscle spasms 3.6 4.6 4.8 5.1 2.4 3.0 Myalgia 3.5 3.6 5.9 8.4 2.7 3.1 Insomnia 3.0 2.8 1.1 5.3 2.8 2.9 Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1 *Adverse Reaction >2% in any dose greater than placebo 6.2 Postmarketing Experience Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The additional events described below have been identified during post-approval use of ezetimibe and/or atorvastatin. Blood and lymphatic system disorders: thrombocytopenia Nervous system disorders: headache; dizziness; paresthesia; peripheral neuropathy There have been rare postmarketing reports of cognitive impairment (e. g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Gastrointestinal disorders: pancreatitis Skin and subcutaneous tissue disorders: angioedema; bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis); rash; urticaria Musculoskeletal and connective tissue disorders: myositis; myopathy/rhabdomyolysis [see Warnings and Precautions ( 5.1 )] There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions ( 5.1 )] . Injury, poisoning and procedural complications: tendon rupture Immune system disorders: anaphylaxis; hypersensitivity reactions Hepatobiliary disorders: hepatitis; cholelithiasis; cholecystitis; fatal and nonfatal hepatic failure Psychiatric disorders: depression Respiratory: interstitial lung disease Laboratory abnormalities: elevated creatine phosphokinase General disorders and administration site conditions: fatigue

4 CONTRAINDICATIONS Active liver disease or unexplained persistent elevations of hepatic transaminase levels. Hypersensitivity to any component of ezetimibe and atorvastatin tablets [see Adverse Reactions ( 6.2 )] . Women who are pregnant or may become pregnant. Ezetimibe and atorvastatin tablets may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and atorvastatin tablets use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. Ezetimibe and atorvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, ezetimibe and atorvastatin tablets should be discontinued immediately, and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )] . Nursing mothers. It is not known whether atorvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe and atorvastatin tablets treatment should not breastfeed their infants [see Use in Specific Populations ( 8.3 )] . Active liver disease or unexplained persistent elevations of hepatic transaminase levels. ( 4 , 5.3 ) Hypersensitivity to any component of LYPQOZET. ( 4 , 6.2 ) Women who are pregnant or may become pregnant. ( 4 , 8.1 ) Nursing mothers. ( 4 , 8.3 )

11 DESCRIPTION LYPQOZET contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and atorvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The molecular formula is C 24 H 21 F 2 NO 3 . Its molecular weight is 409.4. Ezetimibe, USP is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is: Atorvastatin is [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). Atorvastatin calcium, USP is a white to off-white amorphous powder that is very slightly soluble in water, insoluble in acetonitrile, and soluble in methanol. The molecular formula of atorvastatin calcium, USP is (C 33 H 34 FN 2 O 5 ) 2 Ca. The molecular weight of atorvastatin calcium is 1155.37. Its structural formula is: LYPQOZET is available for oral use as tablets containing 10 mg of ezetimibe and: 10.34 mg of atorvastatin calcium, equivalent to 10 mg of atorvastatin (LYPQOZET 10 mg/10 mg); 20.68 mg of atorvastatin calcium, equivalent to 20 mg of atorvastatin (LYPQOZET 10 mg/20 mg); 41.37 mg of atorvastatin calcium, equivalent to 40 mg of atorvastatin (LYPQOZET 10 mg/40 mg); or 82.73 mg of atorvastatin calcium, equivalent to 80 mg of atorvastatin (LYPQOZET 10 mg/80 mg). Each film-coated tablet of LYPQOZET contain the following inactive ingredients: calcium carbonate, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, polysorbate 80, red 30 iron oxide, sodium lauryl sulfate, talc and titanium dioxide. avorstatin-calcium-structure ezetimibe-structure

2 DOSAGE AND ADMINISTRATION Dosage range is 10/10 mg/day through 10/80 mg/day. ( 2.1 ) Recommended starting dose is 10/10 mg/day or 10/20 mg/day. ( 2.1 ) Recommended starting dose is 10/40 mg/day for patients requiring a greater than 55% reduction in LDL-C. ( 2.1 ) Dosing of LYPQOZET should occur either greater than or equal to 2 hours before or greater than or equal to 4 hours after administration of a bile acid sequestrant. ( 2.3 , 7.12 ) 2.1 Recommended Dosing The dosage range of LYPQOZET is 10/10 mg/day to 10/80 mg/day. The recommended starting dose of LYPQOZET is 10/10 mg/day or 10/20 mg/day. LYPQOZET can be administered as a single dose at any time of the day, with or without food. The recommended starting dose for patients who require a larger reduction in LDL-C (greater than 55%) is 10/40 mg/day. After initiation and/or upon titration of LYPQOZET, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly. Patients should swallow LYPQOZET tablets whole. Tablets should not be crushed, dissolved, or chewed. 2.2 Patients with Homozygous Familial Hypercholesterolemia The dosage of LYPQOZET in patients with homozygous familial hypercholesterolemia is 10/40 mg/day or 10/80 mg/day. LYPQOZET should be used as an adjunct to other lipid-lowering treatments (e. g., LDL apheresis) in these patients or if such treatments are unavailable. 2.3 Coadministration with Other Drugs Bile Acid Sequestrants Dosing of LYPQOZET should occur either greater than or equal to 2 hours before or greater than or equal to 4 hours after administration of a bile acid sequestrant [see Drug Interactions ( 7.12 )] . Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with LYPQOZET should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing LYPQOZET and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with LYPQOZET should be limited to 10/20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LYPQOZET is employed. In patients taking hepatitis C antiviral agents containing elbasvir and grazoprevir, therapy with LYPQOZET should not exceed 10/20 mg. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with LYPQOZET should be limited to 10/40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LYPQOZET is employed [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 )] . Other Concomitant Lipid-Lowering Therapy The combination of LYPQOZET and gemfibrozil is not recommended [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.4 )] .

10 OVERDOSAGE LYPQOZET No specific treatment of overdosage with LYPQOZET can be recommended. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Ezetimibe In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks, was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events. Atorvastatin Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

7 DRUG INTERACTIONS [See Clinical Pharmacology ( 12.3 ).] LYPQOZET The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e. g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis with Atorvastatin ( 2.3 , 5.1 , 7 , 12.3 ) Interacting Agents Prescribing Recommendations for LYPQOZET Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil Avoid LYPQOZET HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary. Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir), hepatitis C antiviral agents (elbasvir and grazoprevir) Do not exceed 10/20 mg LYPQOZET daily. HIV protease inhibitor (nelfinavir), hepatitis C protease inhibitor (boceprevir) Do not exceed 10/40 mg LYPQOZET daily. Other lipid-lowering medications: Use with fenofibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with LYPQOZET. ( 7 ) Fenofibrates: Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. ( 7.5 , 12.3 ) Cholestyramine: Combination decreases exposure of ezetimibe. ( 2.3 , 12.3 ) Digoxin: Patients should be monitored appropriately. ( 7.7 ) Oral contraceptives: Values for norethindrone and ethinyl estradiol may be increased. ( 7.8 ) Rifampin should be simultaneously coadministered with LYPQOZET. ( 7.10 ) 7.1 Strong Inhibitors of Cytochrome P450 3A4 Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP3A4. Because LYPQOZET contains atorvastatin, the risk of myopathy during treatment with LYPQOZET is increased with concurrent administration of: Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of 80 mg atorvastatin with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone [see Clinical Pharmacology ( 12.3 )] . Therefore, in patients taking clarithromycin, caution should be used when the LYPQOZET dose exceeds 10/20 mg [see Warnings and Precautions ( 5.1 ) and Dosage and Administration ( 2.3 )] . Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone [see Clinical Pharmacology ( 12.3 )] . Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of LYPQOZET should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing LYPQOZET and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of LYPQOZET should not exceed 10/20 mg and should be used with caution [see Warnings and Precautions ( 5.1 ) and Dosage and Administration ( 2.3 )] . In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of LYPQOZET should not exceed 10/40 mg daily and close clinical monitoring is recommended. Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg [see Clinical Pharmacology ( 12.3 )] . Therefore, in patients taking itraconazole, do not use a LYPQOZET dose that exceeds 10/20 mg [see Warnings and Precautions ( 5.1 ) and Dosage and Administration ( 2.3 )] . 7.2 Cyclosporine Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e. g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone [see Clinical Pharmacology ( 12.3 )] . In addition, ezetimibe and cyclosporine used concomitantly can increase exposure to both ezetimibe and cyclosporine. The degree of increase in ezetimibe exposure may be greater in patients with severe renal impairment. The coadministration of LYPQOZET with cyclosporine should be avoided [see Warnings and Precautions ( 5.1 )] . 7.3 Grapefruit Juice Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day). 7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of LYPQOZET with gemfibrozil should be avoided [see Warnings and Precautions ( 5.1 )] . 7.5 Fenofibrates (e. g., fenofibrate and fenofibric acid) Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fenofibrates, LYPQOZET should be administered with caution when used concomitantly with a fenofibrate [see Warnings and Precautions ( 5.1 )] . Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected in a patient receiving LYPQOZET and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid] . 7.6 Niacin The risk of skeletal muscle effects may be enhanced when LYPQOZET is used in combination with niacin; a reduction in LYPQOZET dosage should be considered in this setting [see Warnings and Precautions ( 5.1 )] . 7.7 Digoxin When multiple doses of atorvastatin and digoxin were coadministered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. 7.8 Oral Contraceptives Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology ( 12.3 )] . These increases should be considered when selecting an oral contraceptive for a woman taking LYPQOZET. 7.9 Elbasvir and Grazoprevir Concomitant administration of elbasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin may be necessary. Coadministration of elbasvir and grazoprevir with atorvastatin increases plasma concentrations of atorvastatin by 1.9-fold due in part to BCRP and/or CYP3A, OATP1B1 inhibition; therefore, the dose of LYPQOZET should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir and grazoprevir [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 )] . 7.10 Rifampin or Other Inducers of Cytochrome P450 3A4 Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e. g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous coadministration of LYPQOZET with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. 7.11 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing LYPQOZET with colchicine. 7.12 Cholestyramine Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. 7.13 Coumarin Anticoagulants If LYPQOZET is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action LYPQOZET Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. LYPQOZET contains ezetimibe and atorvastatin, two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins [see Clinical Studies ( 14 )] . Atorvastatin In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles. 12.2 Pharmacodynamics Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Atorvastatin as well as some of its metabolites are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration ( 2 )] . 12.3 Pharmacokinetics LYPQOZET LYPQOZET has been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets. Absorption Ezetimibe After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Atorvastatin Maximum plasma atorvastatin concentrations after oral administration occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. Effect of Food on Oral Absorption LYPQOZET When LYPQOZET 10/80 tablet was administered with a high-fat meal, atorvastatin C max decreased by 7% and no effect on atorvastatin AUC was observed. A high-fat meal had no effect on the pharmacokinetics of unconjugated ezetimibe. LYPQOZET can be taken with or without food [see Dosage and Administration ( 2.1 )] . Distribution Ezetimibe Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. Atorvastatin Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications ( 4 ); Use in Specific Populations ( 8.3 )] . Metabolism and Excretion Ezetimibe Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of 14 C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. Atorvastatin Atorvastatin is extensively metabolized to ortho- and para hydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and para hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions ( 7.1 )] . In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Specific Populations Geriatric Patients Ezetimibe In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects. Atorvastatin Plasma concentrations of atorvastatin are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults. Pediatric Patients: [See Use in Specific Populations ( 8.4 ).] Gender Ezetimibe In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men. Atorvastatin Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women. Race Ezetimibe Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects. Hepatic Impairment Ezetimibe After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold on both Day 1 and Day 14 when compared to healthy subjects. Atorvastatin In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C max and AUC are each 4-fold greater in patients with Child-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh B disease [see Contraindications ( 4 )] . Renal Impairment [See Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.7 )] Ezetimibe After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m 2 ), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9). Atorvastatin Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin. Hemodialysis Atorvastatin While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins. Drug Interactions [See also Drug Interactions ( 7 ).] No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with atorvastatin. Specific pharmacokinetic drug interaction studies with LYPQOZET have not been performed. Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of LYPQOZET with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of the atorvastatin component of LYPQOZET. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4. Ezetimibe Table 5: Effect of Coadministered Drugs on Total Ezetimibe Coadministered Drug and Dosing Regimen Total Ezetimibe* Change in AUC Change in C max Cyclosporine-stable dose required (75 to 150 mg BID) †,‡ ↑240% ↑290% Fenofibrate, 200 mg QD, 14 days ‡ ↑48% ↑64% Gemfibrozil, 600 mg BID, 7 days ‡ ↑64% ↑91% Cholestyramine, 4 g BID, 14 days ‡ ↓55% ↓4% Aluminum & magnesium hydroxide combination antacid, single dose § ↓4% ↓30% Cimetidine, 400 mg BID, 7 days ↑6% ↑22% Glipizide, 10 mg, single dose ↑4% ↓8% Statins Lovastatin 20 mg QD, 7 days ↑9% ↑3% Pravastatin 20 mg QD, 14 days ↑7% ↑23% Atorvastatin 10 mg QD, 14 days ↓2% ↑12% Rosuvastatin 10 mg QD, 14 days ↑13% ↑18% Fluvastatin 20 mg QD, 14 days ↓19% ↑7% * Based on 10-mg dose of ezetimibe † Post-renal transplant patients with mild impaired or normal renal function. In a different study, a renal transplant patient with severe renal impairment (creatinine clearance of 13.2 mL/min/1.73 m 2 ) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. ‡ See Drug Interactions ( 7 ) § Supralox ® , 20 mL Table 6: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs Coadministered Drug and its Dosage Regimen Ezetimibe Dosage Regimen Change in AUC of Coadministered Drug Change in C max of Coadministered Drug Warfarin, 25 mg single dose on Day 7 10 mg QD, 11 days ↓2% (R-warfarin) ↓4% (S-warfarin) ↑3% (R-warfarin) ↑1% (S-warfarin) Digoxin, 0.5 mg single dose 10 mg QD, 8 days ↑2% ↓7% Gemfibrozil, 600 mg BID, 7 days* 10 mg QD, 7 days ↓1% ↓11% Ethinyl estradiol & Levonorgestrel, QD, 21 days 10 mg QD, Days 8 to14 of 21 d oral contraceptive cycle Ethinyl estradiol 0% Levonorgestrel 0% Ethinyl estradiol ↓9% Levonorgestrel ↓5% Glipizide, 10 mg on Days 1 and 9 10 mg QD, Days 2 to 9 ↓3% ↓5% Fenofibrate, 200 mg QD, 14 days* 10 mg QD, 14 days ↑11% ↑7% Cyclosporine, 100 mg single dose Day 7* 20 mg QD, 8 days ↑15% ↑10% Statins Lovastatin 20 mg QD, 7 days 10 mg QD, 7 days ↑19% ↑3% Pravastatin 20 mg QD, 14 days 10 mg QD, 14 days ↓20% ↓24% Atorvastatin 10 mg QD, 14 days 10 mg QD, 14 days ↓4% ↑7% Rosuvastatin 10 mg QD, 14 days 10 mg QD, 14 days ↑19% ↑17% Fluvastatin 20 mg QD, 14 days 10 mg QD, 14 days ↓39% ↓27% * See Drug Interactions ( 7 ) Atorvastatin Table 7: Effect of Coadministered Drugs on the Pharmacokinetics of Atorvastatin Coadministered Drug and Dosing Regimen Atorvastatin Dose (mg) Change in AUC * Change in C max * Cyclosporine 5.2 mg/kg/day, stable dose † 10 mg QD for 28 days ↑8.7 fold ↑10.7 fold Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days † 10 mg, SD ↑9.4 fold ↑8.6 fold Telaprevir 750 mg q8h, 10 days † 20 mg, SD ↑7.88 fold ↑10.6 fold Saquinavir 400 mg BID/ritonavir 400 mg BID, 15 days †,# 40 mg QD for 4 days ↑3.9 fold ↑4.3 fold Clarithromycin 500 mg BID, 9 days † 80 mg QD for 8 days ↑4.4 fold ↑5.4 fold Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days † 10 mg QD for 4 days ↑3.4 fold ↑2.25 fold Itraconazole 200 mg QD, 4 days † 40 mg, SD ↑3.3 fold ↑20% Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days † 10 mg QD for 4 days ↑2.53 fold ↑2.84 fold Fosamprenavir 1400 mg BID, 14 days † 10 mg QD for 4 days ↑2.3 fold ↑4.04 fold Nelfinavir 1250 mg BID, 14 days † 10 mg QD for 28 days ↑74% ↑2.2 fold Grapefruit Juice, 240 mL QD †,‡ 40 mg, SD ↑37% ↑16% Diltiazem 240 mg QD, 28 days 40 mg, SD ↑51% No change Erythromycin 500 mg QID, 7 days 10 mg, SD ↑33% ↑38% Amlodipine 10 mg, single dose 80 mg, SD ↑15% ↓12% Cimetidine 300 mg QD, 4 weeks 10 mg QD for 2 weeks ↓Less than 1% ↓11% Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓26% § Maalox TC ® 30 mL QD, 17 days 10 mg QD for 15 days ↓33% ↓34% Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓41% ↓1% Rifampin 600 mg QD, 7 days (coadministered) †,¶ 40 mg, SD ↑30% ↑2.7 fold Rifampin 600 mg QD, 5 days (doses separated) †,¶ 40 mg, SD ↓80% ↓40% Gemfibrozil 600 mg BID, 7 days † 40 mg, SD ↑35% ↓Less than 1% Fenofibrate 160 mg QD, 7 days † 40 mg, SD ↑3% ↑2% Boceprevir 800 mg TID, 7 days 40 mg, SD ↑2.30 fold ↑2.66 fold Grazoprevir 200 mg + Elbasvir 50 mg QD, 13 days 10 mg, SD ↑1.9 fold ↑4.34 fold * Data given as x-fold change represent a simple ratio between coadministration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). † See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ) for clinical significance. ‡ Greater increases in AUC (up to 2.5 fold) and/or C max (up to 71%) have been reported with excessive grapefruit consumption (≥750 mL to 1.2 liters per day). § Single sample taken 8 to16 h post-dose. ¶ Due to the dual interaction mechanism of rifampin, simultaneous coadministration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. # The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. Table 8: Effect of Atorvastatin on the Pharmacokinetics of Coadministered Drugs Atorvastatin Coadministered Drug and Dosing Regimen Drug/Dose (mg) Change in AUC Change in C max 80 mg QD for 15 days Antipyrine, 600 mg SD ↑3% ↓11% 80 mg QD for 14 days Digoxin 0.25 mg QD, 20 days* ↑15% ↑20% 40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1 mg - ethinyl estradiol 35 mcg ↑28% ↑19% ↑23% ↑30% 10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change 10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓27% ↓18% 10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change * See Drug Interactions ( 7 ) for clinical significance.

20240124

2

3 DOSAGE FORMS AND STRENGTHS LYPQOZET is available as follows: 10 mg/10 mg - White to off white, oval shaped film-coated tablets, debossed with “W 10” on one side and plain on other side containing 10 mg of ezetimibe, USP and 10.34 mg of atorvastatin calcium, USP, equivalent to 10 mg of atorvastatin. 10 mg/20 mg - White to off white, oval shaped film-coated tablets, debossed with “W 20” on one side and plain on other side containing 10 mg of ezetimibe, USP and 20.68 mg of atorvastatin calcium, USP, equivalent to 20 mg of atorvastatin. 10 mg/40 mg - White to off white, oval shaped film-coated tablets, debossed with “W 40” on one side and plain on other side containing 10 mg of ezetimibe, USP and 41.37 mg of atorvastatin calcium, USP, equivalent to 40 mg of atorvastatin. 10 mg/80 mg - White to off white, oval shaped film-coated tablets, debossed with “W 80” on one side and plain on other side containing 10 mg of ezetimibe, USP and 82.73 mg of atorvastatin calcium, USP, equivalent to 80 mg of atorvastatin. Tablets (ezetimibe mg/atorvastatin mg): 10/10, 10/20, 10/40, 10/80. ( 3 )

LYPQOZET (ezetimibe and atorvastatin) EZETIMIBE EZETIMIBE ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN CALCIUM CARBONATE SILICON DIOXIDE CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 8000 POLYSORBATE 80 FERRIC OXIDE RED SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE W;10 LYPQOZET (ezetimibe and atorvastatin) EZETIMIBE EZETIMIBE ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN CALCIUM CARBONATE SILICON DIOXIDE CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 8000 POLYSORBATE 80 FERRIC OXIDE RED SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE W;20 LYPQOZET (ezetimibe and atorvastatin) EZETIMIBE EZETIMIBE ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN CALCIUM CARBONATE SILICON DIOXIDE CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 8000 POLYSORBATE 80 FERRIC OXIDE RED SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE W;40 LYPQOZET (ezetimibe and atorvastatin) EZETIMIBE EZETIMIBE ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN CALCIUM CARBONATE SILICON DIOXIDE CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 8000 POLYSORBATE 80 FERRIC OXIDE RED SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE W;80

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and atorvastatin. The combination of ezetimibe with atorvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and atorvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 250 mg/kg with the combination of ezetimibe and atorvastatin (1:1) in the in vivo mouse micronucleus test. Ezetimibe A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Atorvastatin In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC 0-24hr value of approximately 16 times the mean human plasma drug exposure after an 80-mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC 0-24hr values of approximately 6 times the mean human plasma drug exposure after an 80-mg oral dose. In vitro , atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli , the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80-mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years. 13.2 Animal Toxicology and/or Pharmacology Ezetimibe In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) was administered intraduodenally, the metabolite was as potent as ezetimibe in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug. In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively. A series of acute preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14 C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D. In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

ANDA206084

LYPQOZET

(ezetimibe and atorvastatin)

70661-006

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL DISPLAY PANEL – 10 mg/10 mg NDC 70661 -005- 30 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/10 mg 30 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 10.34 mg of atorvastatin calcium, USP, equivalent to 10 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by : Althera Pharmaceuticals, LLC, Wilmington, DE 19801 USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15757 XXXXXXX NDC 70661 -005- 90 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/10 mg 90 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 10.34 mg of atorvastatin calcium, USP, equivalent to 10 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15759 XXXXXXX PACKAGE/LABEL DISPLAY PANEL – 10 mg/20 mg NDC 70661 -006- 30 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/20 mg 30 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 20.68 mg of atorvastatin calcium, USP, equivalent to 20 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by: Althera Pharmaceuticals LLC, Wilmington, DE 19801 USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15760 XXXXXXX NDC 70661 -006- 90 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/20 mg 90 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 20.68 mg of atorvastatin calcium, USP, equivalent to 20 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15760 XXXXXXX PACKAGE/LABEL DISPLAY PANEL – 10 mg/40 mg NDC 70661 -007- 30 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/40 mg 30 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 41.37 mg of atorvastatin calcium, USP, equivalent to 40 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by: Althera Pharmaceuticals, LLC, Wilmington, DE, 19801, USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15761 XXXXXXX NDC 70661 -007- 90 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/40 mg 90 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 41.37 mg of atorvastatin calcium, USP, equivalent to 40 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by: Althera Pharmaceuticals LLC, Wilmington, DE 19801 USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15762 XXXXXXX PACKAGE/LABEL DISPLAY PANEL – 10 mg/80 mg NDC 70661 -008- 30 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/80 mg 30 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 82.73 mg of atorvastatin calcium, USP, equivalent to 80 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15763 XXXXXXX NDC 70661 -008- 90 LYPQOZET (ezetimibe and atorvastatin) tablets 10 mg/80 mg 90 Tablets Rx Only Each Film-Coated Tablet Contains: 10 mg of ezetimibe, USP and 82.73 mg of atorvastatin calcium, USP, equivalent to 80 mg of atorvastatin. Dispense in a tight, light resistant container as defined in the USP. Keep out of reach of children. Usual Adult Dosage: See package outsert for full Prescribing Information. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Distributed by: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 USA Manufactured for: Althera Pharmaceuticals, LLC, Wilmington, DE 19801 MADE IN INDIA CODE: MP/DRUGS/25/10/92 Rev. 01/2024 EM 15764 XXXXXXX label-10-10-30 label-10-10-90 label-10-20-30 label-10-20-90 label-10-40-30 label-10-40-90 label-10-80-30 label-10-80-90

Warnings and Precautions Myopathy/Rhabdomyolysis ( 5.1 ) 09/2020 Immune-Mediated Necrotizing Myopathy ( 5.2 ) 09/2020

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-Approved Patient Labeling (Patient Information). Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. 17.1 Muscle Pain All patients starting therapy with LYPQOZET should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing LYPQOZET. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. Patients should discuss all medication, both prescription and over-the-counter, with their physician. 17.2 Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of LYPQOZET and if signs or symptoms of liver injury occur. All patients treated with LYPQOZET should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using LYPQOZET. Discuss future pregnancy plans with your patients, and discuss when to stop taking LYPQOZET if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking LYPQOZET and call their healthcare professional. 17.4 Breastfeeding Women who are breastfeeding should be advised to not use LYPQOZET. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals. 17.5 Important Storage and Administration Instructions Patients should be advised to see the FDA-Approved Patient Labeling (Patient Information). Tablets should be swallowed whole. Do not crush, dissolve, or chew tablets. If a dose is missed, the patient should not take an extra dose. Just resume the usual schedule. Brands listed are the trademarks of their respective owners. Manufacturer for: Althera Pharmaceuticals, LLC., 1201 N Orange St, Suite 712, Wilmington, DE 19801 Distributed by: Althera Pharmaceuticals, LLC., Wilmington, DE 19801 USA Revised: January 2024

14 CLINICAL STUDIES 14.1 Primary Hyperlipidemia Ezetimibe and Atorvastatin Tablets - Lipid Efficacy Ezetimibe and atorvastatin tablets reduce total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with hypercholesterolemia. Ezetimibe and atorvastatin tablets are effective in men and women with hyperlipidemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of ezetimibe and atorvastatin tablets. In a multicenter, double-blind, placebo-controlled, clinical study in patients with hyperlipidemia, 628 patients were treated for up to 12 weeks and 246 for up to an additional 48 weeks. Patients were randomized to receive placebo, ezetimibe (10 mg), atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or coadministered ezetimibe and atorvastatin equivalent to ezetimibe and atorvastatin tablets (10/10, 10/20, 10/40, and 10/80) in the 12-week study. After completing the 12-week study, patients who agreed to participate in the study extension were assigned to coadministered ezetimibe and atorvastatin equivalent to ezetimibe and atorvastatin tablets (10/10 to 10/80) or atorvastatin (10 to 80 mg/day) for an additional 48 weeks. The patient population was: 59% female; 85% Caucasian, 6% Black, 3% Asian, 5% Hispanic, 1% American Indian, <1% other; 18 to 86 years of age (mean age 57 years). Patients receiving all doses of ezetimibe and atorvastatin tablets were compared to those receiving all doses of atorvastatin. Ezetimibe and atorvastatin tablets lowered total-C, LDL-C, Apo B, TG, and non-HDL-C, and increased HDL-C significantly more than atorvastatin alone. (See Table 9.) Table 9: Response to Ezetimibe and Atorvastatin Tablets in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline † at 12 weeks) Treatment (Daily Dose) N Total-C [Baseline § ] LDL-C [Baseline § ] Apo B [Baseline § ] TG* [Baseline § ] HDL-C [Baseline § ] Non-HDL-C [Baseline § ] Pooled data (All ezetimibe and atorvastatin tablets doses) ‡ 255 -41% [267] -56% [182] -45% [170] -33% [165] +7% [50.8] -52% [217] Pooled data (All atorvastatin doses) ‡ 248 -32% [269] -44% [181] -36% [168] -24% [155] +4% [53.7] -41% [215] Ezetimibe 10 mg 65 -14% [259] -20% [177] -15% [167] -5% [145] +4% [50.6] -18% [209] Placebo 60 +4% [262] +4% [180] +3% [168] -6% [143] +4% [50.4] +4% [212] Ezetimibe and atorvastatin tablets by dose 10/10 65 -38% [262] -53% [177] -43% [165] -31% [158] +9% [51.9] -49% [211] 10/20 62 -39% [269] -54% [184] -44% [174] -30% [165] +9% [49.3] -50% [220] 10/40 65 -42% [271] -56% [184] -45% [173] -34% [180] +5% [51.1] -52% [220] 10/80 63 -46% [267] -61% [183] -50% [169] -40% [146] +7% [50.9] -58% [216] Atorvastatin by dose 10 mg 60 -26% [271] -37% [185] -28% [168] -21% [153] +6% [53.7] -34% [217] 20 mg 60 -30% [267] -42% [177] -34% [164] -23% [147] +4% [55.5] -39% [211] 40 mg 66 -32% [266] -45% [180] -37% [167] -24% [159] +4% [53.0] -41% [213] 80 mg 62 -40% [270] -54% [184] -46% [171] -31% [163] +3% [52.7] -51% [218] * For triglycerides, median % change from baseline † Baseline - on no lipid-lowering drug ‡ Ezetimibe and atorvastatin tablets pooled (10/10 to 10/80) significantly reduced total-C, LDL-C, Apo B, TG, non-HDL-C, and significantly increased HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg). § Baseline units: mg/dL; medians for TG, means for all other values The changes in lipid endpoints after an additional 48 weeks of treatment with ezetimibe and atorvastatin tablets (all doses) or with atorvastatin (all doses) were generally consistent with the 12-week data displayed above in the 245 subjects (out of the 576 who completed the 12-week study) who agreed to participate in the study extension. A multicenter, double-blind, controlled, 14-week study was conducted in 621 patients with heterozygous familial hypercholesterolemia (HeFH), coronary heart disease (CHD), or multiple cardiovascular risk factors (≥2), adhering to an NCEP Step I or stricter diet. All patients received atorvastatin 10 mg for a minimum of 4 weeks prior to randomization. Patients were then randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to ezetimibe and atorvastatin tablets 10/10) or atorvastatin 20 mg/day monotherapy. Patients who did not achieve their LDL-C target goal after 4 and/or 9 weeks of randomized treatment were titrated to double the atorvastatin dose. The patient population was: 47% female; 91% Caucasian, 2% Black, 2% Asian, 5% Hispanic, <1% other; 18 to 82 years of age (mean age 61 years). Ezetimibe and atorvastatin tablets 10/10 was significantly more effective than doubling the dose of atorvastatin to 20 mg in further reducing total-C, LDL-C, TG, and non-HDL-C. Results for HDL-C between the two treatment groups were not significantly different. (See Table 10.) In addition, at Week 4 significantly more patients receiving ezetimibe and atorvastatin tablets 10/10 attained LDL-C <100 mg/dL (<2.6 mmol/L) compared to those receiving atorvastatin 20 mg, 12% vs. 2%. The baseline mean LDL-C levels for patients receiving ezetimibe and atorvastatin tablets 10/10 and atorvastatin 20 mg were 186 mg/dL and 187 mg/dL, respectively. Table 10: Response to Ezetimibe and Atorvastatin Tablets after 4 Weeks in Patients with CHD or Multiple Cardiovascular Risk Factors and an LDL-C ≥130 mg/dL (Mean* % Change from Baseline † ) Treatment (Daily Dose) N Total-C [Baseline ‡ ] LDL-C [Baseline ‡ ] HDL-C [Baseline ‡ ] TG* [Baseline ‡ ] Non-HDL-C [Baseline ‡ ] Ezetimibe and atorvastatin tablets 10/10 305 -17% § [262] -24% § [186] +2% [50.0] -9% § [117] -22% § [212] Atorvastatin 20 mg 316 -6% [264] -9% [187] +1% [49.9] -4% [119] -8% [214] * For triglycerides, median % change from baseline † Patients on atorvastatin 10 mg, then switched to ezetimibe and atorvastatin tablets 10/10 or titrated to atorvastatin 20 mg ‡ Baseline units: mg/dL; medians for TG, means for all other values § p<0.05 for difference with atorvastatin The Titration of Atorvastatin Versus Ezetimibe Add-On to Atorvastatin in Patients with Hypercholesterolemia (TEMPO) study, a multicenter, double-blind, controlled, 6-week study, included 184 patients with an LDL-C level ≥100 mg/dL and ≤160 mg/dL (≥2.6 mmol/L and ≤4.1 mmol/L) and at moderate high risk for coronary heart disease (CHD). All patients received atorvastatin 20 mg for a minimum of 4 weeks prior to randomization. Patients not at the optional NCEP ATP III LDL-C level (<100 mg/dL [<2.6 mmol/L]) were randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to ezetimibe and atorvastatin tablets 10/20) or atorvastatin 40 mg for 6 weeks. The patient population was: 45% female; 60% Caucasian, 26% Multi-racial, 6% Black, 8% Asian, <1% American Indian or Alaska native; 24 to 78 years of age (mean age 58 years). Ezetimibe and atorvastatin tablets 10/20 was significantly more effective than doubling the dose of atorvastatin to 40 mg in further reducing total-C, LDL-C, Apo B and non-HDL-C. Results for HDL-C and TG between the two treatment groups were not significantly different. (See Table 11.) In addition, significantly more patients receiving ezetimibe and atorvastatin tablets 10/20 attained LDL-C <100 mg/dL (<2.6 mmol/L) compared to those receiving atorvastatin 40 mg, 84% vs. 49%. Table 11: Response to Ezetimibe and Atorvastatin Tablets in Patients with Primary Hypercholesterolemia (Mean* % Change from Baseline † ) Treatment (Daily Dose) N Total-C [Baseline ‡ ] LDL-C [Baseline ‡ ] Apo B [Baseline ‡ ] HDL-C [Baseline ‡ ] TG* [Baseline ‡ ] Non-HDL-C [Baseline ‡ ] Ezetimibe and atorvastatin tablets 10/20 92 -20% § [203] -31% § [120] -21% § [123] +3% [50.9] -18% [155] -27% § [152] Atorvastatin 40 mg 92 -7% [201] -11% [118] -8% [120] +1% [52.1] -6% [148] -10% [149] * For triglycerides, median % change from baseline † Patients on atorvastatin 20 mg, then switched to ezetimibe and atorvastatin tablets 10/20 or titrated to atorvastatin 40 mg ‡ Baseline units: mg/dL; medians for TG, means for all other values § p<0.05 for difference with atorvastatin The Ezetimibe Plus Atorvastatin Versus Atorvastatin Titration in Achieving Lower LDL-C Targets in Hypercholesterolemic Patients (EZ-PATH) study, a multicenter, double-blind, controlled, 6-week study, included 556 patients with an LDL-C level ≥70 mg/dL and ≤160 mg/dL (≥1.8 mmol/L and ≤4.1 mmol/L) and at high risk for coronary heart disease (CHD). All patients received atorvastatin 40 mg for a minimum of 4 weeks prior to randomization. Patients not at the optional NCEP ATP III LDL-C level <70 mg/dL (<1.8 mmol/L) were randomized to receive either coadministered ezetimibe and atorvastatin (equivalent to ezetimibe and atorvastatin tablets 10/40) or atorvastatin 80 mg for 6 weeks. The patient population was: 39% female; 81% Caucasian, 11% Black, 6% Multi-racial, 2% Asian; 31 to 80 years of age (mean age 52 years). Ezetimibe and atorvastatin tablets 10/40 was significantly more effective than doubling the dose of atorvastatin to 80 mg in further reducing total-C, LDL-C, Apo B, TG, and non-HDL-C. Results for HDL-C between the two treatment groups were not significantly different. (See Table 12.) In addition, significantly more patients receiving ezetimibe and atorvastatin tablets 10/40 attained LDL-C <70 mg/dL (<1.8 mmol/L) compared to those receiving atorvastatin 80 mg, 74% vs. 32%. Table 12: Response to Ezetimibe and Atorvastatin Tablets in Patients with Primary Hypercholesterolemia (Mean* % Change from Baseline † ) Treatment (Daily Dose) N Total-C [Baseline ‡ ] LDL-C [Baseline ‡ ] Apo B [Baseline ‡ ] HDL-C [Baseline ‡ ] TG* [Baseline ‡ ] Non-HDL-C [Baseline ‡ ] Ezetimibe and atorvastatin tablets 10/40 277 -17% § [165] -27% § [89] -18% § [101] 0% [47.7] -12% § [131] -23% § [117] Atorvastatin 80 mg 279 -7% [165] -11% [90] -8% [102] -1% [46.9] -6% [136] -9% [118] * For triglycerides, median % change from baseline † Patients on atorvastatin 20 mg, then switched to ezetimibe and atorvastatin tablets 10/40 or titrated to atorvastatin 80 mg ‡ Baseline units: mg/dL; medians for TG, means for all other values § p<0.05 for difference with atorvastatin 14.2 Homozygous Familial Hypercholesterolemia (HoFH) A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=36) receiving atorvastatin 40 mg at baseline. Increasing the dose of atorvastatin from 40 to 80 mg (n=12) produced a reduction of LDL-C of 2% from baseline on atorvastatin 40 mg. Coadministered ezetimibe and atorvastatin equivalent to ezetimibe and atorvastatin tablets (10/40 and 10/80 pooled, n=24), produced a reduction of LDL-C of 19% from baseline on atorvastatin 40 mg. In those patients coadministered ezetimibe and atorvastatin equivalent to ezetimibe and atorvastatin tablets (10/80, n=12), a reduction of LDL-C of 25% from baseline on atorvastatin 40 mg was produced. After completing the 12-week study, eligible patients (n=35), who were receiving atorvastatin 40 mg at baseline, were assigned to coadministered ezetimibe and atorvastatin equivalent to ezetimibe and atorvastatin tablets 10/40 for up to an additional 24 months. Following at least 4 weeks of treatment, the atorvastatin dose could be doubled to a maximum dose of 80 mg. At the end of the 24 months, ezetimibe and atorvastatin tablets (10/40 and 10/80 pooled) produced a reduction of LDL-C that was consistent with that seen in the 12-week study.

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. ( 8.6 , 12.3 ) 8.1 Pregnancy Pregnancy Category X. [See Contraindications ( 4 ).] Ezetimibe and Atorvastatin Tablets Ezetimibe and atorvastatin tablets are contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of ezetimibe and atorvastatin tablets use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Statins may cause fetal harm when administered to a pregnant woman. Because ezetimibe and atorvastatin tablets contain atorvastatin, ezetimibe and atorvastatin tablets should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking ezetimibe and atorvastatin tablets, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy. Ezetimibe In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. Atorvastatin Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m 2 ). In a study in rats given 20, 100, or 225 mg/kg/day, from gestation Day 7 through to lactation Day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on Days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at Days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotarod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Rare reports of congenital anomalies have been received following intrauterine exposure to statin reductase inhibitors. 8.3 Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk. It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver atorvastatin levels of 50% and 40%, respectively, of that in their mother’s milk. Because of the potential for adverse reactions in nursing infants, women taking ezetimibe and atorvastatin tablets should not breastfeed [see Contraindications ( 4 )] . 8.4 Pediatric Use Ezetimibe and Atorvastatin Tablets Safety and effectiveness have not been established in pediatric patients. Ezetimibe Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available. Atorvastatin Pharmacokinetic data in the pediatric population are not available. 8.5 Geriatric Use Of the patients who received ezetimibe coadministered with atorvastatin in clinical studies, 1166 were 65 and older (this included 291 who were 75 and older). The effectiveness and safety of ezetimibe and atorvastatin tablets were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, ezetimibe and atorvastatin tablets should be prescribed with caution in the elderly [see Clinical Pharmacology ( 12.3 )] . In geriatric patients, no dosage adjustment of ezetimibe and atorvastatin tablets is necessary. 8.6 Hepatic Impairment Ezetimibe and atorvastatin tablets are contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 ), and Clinical Pharmacology ( 12.3 )] . 8.7 Renal Impairment A history of renal impairment may be a risk factor for statin-associated myopathy. These patients merit closer monitoring for skeletal muscle effects [see Warnings and Precautions ( 5.1 )] . In patients with renal impairment, no dosage adjustment of ezetimibe and atorvastatin tablets is necessary.

16 HOW SUPPLIED/STORAGE AND HANDLING LYPQOZET is available as follows: 10 mg/10 mg - White to off white, oval shaped film-coated tablets, debossed with “W 10” on one side and plain on other side containing 10 mg of ezetimibe, USP and 10.34 mg of atorvastatin calcium, USP, equivalent to 10 mg of atorvastatin. Bottles of 30 ……………………………….70661-005-30 Bottles of 90 ……………………………….70661-005-90 10 mg/20 mg - White to off white, oval shaped film-coated tablets, debossed with “W 20” on one side and plain on other side containing 10 mg of ezetimibe, USP and 20.68 mg of atorvastatin calcium, USP, equivalent to 20 mg of atorvastatin. Bottles of 30 ……………………………….70661-006-30 Bottles of 90 ……………………………….70661-006-90 10 mg/40 mg – White to off white, oval shaped film-coated tablets, debossed with “W 40” on one side and plain on other side containing 10 mg of ezetimibe, USP and 41.37 mg of atorvastatin calcium, USP, equivalent to 40 mg of atorvastatin. Bottles of 30 ……………………………….70661-007-30 Bottles of 90 ……………………………….70661-007-90 10 mg/80 mg – White to off white, oval shaped film-coated tablets, debossed with “W 80” on one side and plain on other side containing 10 mg of ezetimibe, USP and 82.73 mg of atorvastatin calcium, USP, equivalent to 80 mg of atorvastatin. Bottles of 30 ……………………………….70661-008-30 Bottles of 90 ……………………………….70661-008-90 Dispense in a tight, light-resistant container as defined in the USP. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (between 59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and light.