ATORVALIQ

1 INDICATIONS AND USAGE ATORVALIQ is indicated: • To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. • As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). • As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia. ATORVALIQ is an HMG-CoA reductase inhibitor (statin) indicated ( 1 ): • To reduce the risk of: o Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. o MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. o Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, congestive heart failure (CHF), and angina in adults with clinically evident CHD. • As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: o Adults with primary hyperlipidemia. o Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. • As an adjunct to diet for the treatment of adults with: o Primary dysbetaliproteinemia. o Hypertriglyceridemia.

2 DOSAGE AND ADMINISTRATION • Take orally once daily, only on an empty stomach ( 2.1 ). • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ATORVALIQ, and adjust dosage if necessary ( 2.1 ). • Adults ( 2.2 ): o Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily. o Patients requiring LDL-C reduction >45% may start at 40 mg once daily. • Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily ( 2.3 ). • Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily ( 2.4 ). • See full prescribing information for ATORVALIQ dosage modifications due to drug interactions ( 2.5 ). 2.1 Important Dosage and Administration Information • Measure the ATORVALIQ dose using a calibrated oral syringe or other oral dosing device scored using metric units of measurements (i.e., mL). • Take ATORVALIQ orally once daily at any time of day, only on an empty stomach (1 hour before or 2 hours after a meal). • Advise patients to take a missed dose as soon as possible. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose. • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ATORVALIQ, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended starting dose of ATORVALIQ is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended starting dosage of ATORVALIQ is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. 2.4 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH The recommended starting dosage of ATORVALIQ is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of ATORVALIQ with the following drugs requires dosage modification of ATORVALIQ [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . Anti-Viral Medications • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed ATORVALIQ 20 mg once daily. • In patients taking nelfinavir, do not exceed ATORVALIQ 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics • In patients taking clarithromycin or itraconazole, do not exceed ATORVALIQ 20 mg once daily. For additional recommendations regarding concomitant use of ATORVALIQ with other anti-viral medications, azole antifungals or macrolide antibiotics, [see Drug Interactions (7.1)] .

5 WARNINGS AND PRECAUTIONS • Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ATORVALIQ dosage. Discontinue ATORVALIQ if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ATORVALIQ in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing ATORVALIQ dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 2.5 , 5.1 , 7.1 , 8.5 , 8.6 ). • Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue ATORVALIQ if IMNM is suspected ( 5.2 ). • Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ATORVALIQ ( 5.3 ). 5.1 Myopathy and Rhabdomyolysis ATORVALIQ may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including ATORVALIQ. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher ATORVALIQ dosage [see Drug Interactions (7.1) and Use in Specific Populations (8.5 , 8.6) ] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis ATORVALIQ exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with ATORVALIQ is not recommended. ATORVALIQ dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2.5) ] . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir [see Adverse Reactions (6.1) ] . Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1) ] . Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking ATORVALIQ [see Drug Interactions (7.1) ] . Discontinue ATORVALIQ if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if ATORVALIQ is discontinued. Temporarily discontinue ATORVALIQ in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the ATORVALIQ dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing My…

4 CONTRAINDICATIONS ATORVALIQ is contraindicated in patients with: • Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] • Hypersensitivity to atorvastatin or any excipients in ATORVALIQ. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6.2) ] . • Acute liver failure or decompensated cirrhosis ( 4 ). • Hypersensitivity to atorvastatin or any excipient in ATORVALIQ ( 4 ).

7 DRUG INTERACTIONS • See full prescribing information for details regarding concomitant use of ATORVALIQ with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis ( 2.5 , 7.1 ). • Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with ATORVALIQ ( 7.2 ). • Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( 7.3 ). • Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.3 ). 7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with ATORVALIQ Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with ATORVALIQ Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3) ] . Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with ATORVALIQ. Intervention: Concomitant use of cyclosporine or gemfibrozil with ATORVALIQ is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of ATORVALIQ with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3) ] . Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention: • Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with ATORVALIQ is not recommended. • In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with ATORVALIQ. • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed ATORVALIQ 20 mg. • In patients taking nelfinavir, do not exceed ATORVALIQ 40 mg [see Dosage and Administration (2.5) ]. • Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with ATORVALIQ. • Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of ATORVALIQ with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3) ] . Intervention: In patients taking clarithromycin or itraconazole, do not exceed ATORVALIQ 20 mg [see Dosage and Administration (2.5) ] . Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with ATORVALIQ. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: …

8.1 Pregnancy Risk Summary Discontinue ATORVALIQ when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ATORVALIQ may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data ) . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. 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 at the MRHD based on surface area (mg/m 2 ). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased. In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through t…

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: • Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] • Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] • Hepatic Dysfunction [see Warnings and Precautions (5.3) ] • Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact CMP Pharma, Inc. at 1-844-321-1443, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ATORVALIQ has been established in adequate and well-controlled trials of atorvastatin calcium tablets, referenced below as “atorvastatin” [see Clinical Studies (14) ]. In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin vs. 7,311 placebo; age range 10-93 years, 39% women, 91% White, 3% Black, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8,755), from seventeen placebo-controlled trials. Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin-Treated with any Dose and Greater than Placebo Adverse Reaction % Placebo N=7,311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8,755 Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3 Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9 Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8 Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0 Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7 Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7 Nausea 3.5 3.7 3.7 7.1 3.8 4.0 Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8 Muscle spasms 3.0 4.6 4.8 5.1 2.4 3.6 Myalgia 3.1 3.6 5.9 8.4 2.7 3.5 Insomnia 2.9 2.8 1.1 5.3 2.8 3.0 Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3 Other adverse reactions reported in placebo-controlled studies include: Body as a whole: malaise, pyrexia Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia Nervous system: nightmare Respiratory system: epistaxis Skin and appendages: urticaria Special senses: vision blurred, tinnitus Urogenital system: white blood cells urine positive Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin. Treating to New Targets Study …