ZYPITAMAG

1 INDICATIONS AND USAGE ZYPITAMAG is indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. Pediatric use information is approved for Kowa Co Ltd LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd marketing exclusivity rights, this drug product is not labeled with that information. ZYPITAMAG is a HMG-CoA reductase inhibitor (statin) indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia ( 1 ).

2 DOSAGE AND ADMINISTRATION Take orally once daily with or without food at the same time each day. ( 2.1 ). For patients requiring a high-intensity statin or are unable to achieve their LDL-C goal receiving ZYPITAMAG 4 mg daily, prescribe alternative LDL-C-lowering treatment. ( 2.1 ) Assess LDL-C when clinically appropriate, as early as 4 weeks after initiation of ZYPITAMAG, and adjust the dosage if necessary. ( 2.1 ) Recommended dosage is 2 mg to 4 mg once daily. Maximum recommended dosage is 4 mg once daily. ( 2.2 ) Recommended starting dosage for patients with moderate and severe renal impairment and end-stage renal disease on hemodialysis is 1 mg once daily. ZYPITAMAG is not available in a 1 mg dose; use an alternative formulation of pitavastatin. Maximum recommended dosage is 2 mg once daily. ( 2.3 ) See full prescribing information for ZYPITAMAG dosage modifications due to drug interactions. ( 2.4 ) 2.1 Important Dosage and Administration Information Take ZYPITAMAG orally once daily with or without food at the same time each day. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ZYPITAMAG 4 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZYPITAMAG, and adjust the dosage if necessary. 2.2 Recommended Dosage for Adults The recommended dosage range of ZYPITAMAG is 2 mg to 4 mg daily. The maximum recommended dosage is ZYPITAMAG 4 mg once daily. 2.3 Recommended Dosage in Patients with Renal Impairment The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 – 59 mL/minute/1.73 m 2 and 15 – 29 mL/minute/1.73 m 2 , respectively) and patients with end-stage renal disease receiving hemodialysis is pitavastatin 1 mg once daily. ZYPITAMAG is not available in a 1 mg dose; use an alternative formulation of pitavastatin for the 1 mg dose. The maximum recommended dose for these patients is ZYPITAMAG 2 mg once daily [see Use in Specific Populations ( 8.6 )] . There are no dosage adjustment recommendations for patients with mild renal impairment. 2.4 Dosage Adjustments Due to Drug Interactions In patients taking erythromycin, do not exceed pitavastatin 1 mg once daily [see Drug Interactions ( 7 )] . ZYPITAMAG is not available in a 1 mg dose; use an alternative formulation of pitavastatin for the 1 mg dose. In patients taking rifampin, do not exceed ZYPITAMAG 2 mg once daily [see Drug Interactions ( 7 )] . Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information. 2.1 Important Dosage and Administration Information Take ZYPITAMAG orally once daily with or without food at the same time each day. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ZYPITAMAG 4 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZYPITAMAG, and adjust the dosage if necessary. 2.2 Recommended Dosage for Adults The recommended dosage range of ZYPITAMAG is 2 mg to 4 mg daily. The maximum recommended dosage is ZYPITAMAG 4 mg once daily. 2.3 Recommended Dosage in Patients with Renal Impairment The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 – 59 mL/minute/1.73 m 2 and 15 – 29 mL/minute/1.73 m 2 , respectively) and patients with end-stage renal disease receiving hemodialysis is pitavastatin 1 mg once daily. ZYPITAMAG is not available in a 1 mg dose; use an alternative formulation of pitavastatin for the 1 mg dose. The maximum recommended dose for these patients is ZYPITAMAG 2 mg once daily [see Use in Specific Populations ( 8.6 )] . There are no dosage adjustment recommendations for patients with mild rena…

5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ZYPITAMAG dosage. Discontinue ZYPITAMAG if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ZYPITAMAG 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 the ZYPITAMAG dosage. Instruct patients to promptly report unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever ( 5.1 , 7 , 8.5 , 8.6 ). Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue ZYPITAMAG 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 enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ZYPITAMAG. ( 5.3 ) 5.1 Myopathy and Rhabdomyolysis ZYPITAMAG 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 pitavastatin. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use of certain drugs (including other lipid-lowering therapies), and higher ZYPITAMAG dosage [see Dosage and Administration ( 2.2 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.5 , 8.6 )] . Dosages of pitavastatin greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of ZYPITAMAG is 4 mg once daily. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis ZYPITAMAG is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil [see Contraindications ( 4 ) and Drug Interactions ( 7 )] . There are pitavastatin dosage restrictions for patients taking erythromycin or rifampin [see Dosage and Administration ( 2.4 )] . The following drugs when used concomitantly with ZYPITAMAG may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1 grams/day), fibrates, and colchicine [see Drug Interactions ( 7 )] . Discontinue ZYPITAMAG if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if ZYPITAMAG is discontinued. Temporarily discontinue ZYPITAMAG 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 ZYPITAMAG 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 Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and …

4 CONTRAINDICATIONS ZYPITAMAG is contraindicated in the following conditions: Concomitant use of cyclosporine [see Drug Interactions ( 7 )] . Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )] Hypersensitivity to pitavastatin or any excipients in ZYPITAMAG. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with pitavastatin [see Adverse Reactions ( 6 )] . Cyclosporine ( 4 , 7 ) Active liver failure or decompensated cirrhosis ( 4 , 5.3 ) Hypersensitivity to pitavastatin or any excipients in ZYPITAMAG ( 4 )

7 DRUG INTERACTIONS See full prescribing information for details regarding concomitant use of ZYPITAMAG with other drugs that increase the risk of myopathy and rhabdomyolysis. ( 2.4 , 7 ). Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with ZYPITAMAG and instructions for preventing or managing drug interactions [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )] . Table 2. Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with ZYPITAMAG Cyclosporine Clinical Impact: Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis . Intervention: Concomitant use of cyclosporine with ZYPITAMAG is contraindicated [see Contraindications ( 4 )]. Gemfibrozil Clinical Impact: Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with statins, including pitavastatin. Intervention: Avoid concomitant use of gemfibrozil with ZYPITAMAG. Erythromycin Clinical Impact: Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis . Intervention: In patients taking erythromycin, do not exceed ZYPITAMAG 1 mg once daily [see Dosage and Administration ( 2.4 )]. Rifampin Clinical Impact: Rifampin significantly increases peak pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis . Intervention: In patients taking rifampin, do not exceed ZYPITAMAG 2 mg once daily [see Dosage and Administration ( 2.4 )]. Fibrates Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins, including pitavastatin. Intervention: Consider if the benefit of using fibrates concomitantly with ZYPITAMAG outweighs the increased risk of myopathy and rhabdomyolysis. Niacin Clinical Impact: The risk of myopathy and rhabdomyolysis may be increased with concomitant use of lipid-modifying doses (1 g/day) of niacin with pitavastatin. Intervention: Consider if the benefit of using lipid-modifying doses (>1 g/day) of niacin concomitantly with ZYPITAMAG outweighs the increased risk of myopathy and rhabdomyolysis. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with statins, including pitavastatin. Intervention: Consider the risk/benefit of concomitant use of colchicine with ZYPITAMAG.

8.1 Pregnancy Risk Summary Discontinue ZYPITAMAG when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. ZYPITAMAG decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ZYPITAMAG 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 statin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) . In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed in pregnant rats or rabbits orally administered pitavastatin during the period of organogenesis at doses that resulted in 22 and 4 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 4 mg, based on AUC (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% to 4% and 15% to 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 use of a statin, and a lack of information on non-live births. Animal Data Embryo-fetal developmental studies were conducted in pregnant rats administered 3 mg/kg/day, 10 mg/kg/day, 30 mg/kg/day pitavastatin by oral gavage during organogenesis (gestation day 7-17). No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC. Embryo-fetal developmental studies were conducted in pregnant rabbits administered 0.1 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis (gestation day 6-18). Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at 4 mg/day based on AUC). In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day, 30 mg/kg/day from organogenesis through weaning (gestation day 17 to lactation d…

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in other sections of 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 )] . The most frequent adverse reactions (rate ≥ 2%) were myalgia, constipation, diarrhea, back pain, and pain in extremity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Medicure at 1-800-509-0544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of one drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults with Primary Hyperlipidemia In 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia were administered pitavastatin 1 mg to 4 mg daily. The mean continuous exposure of pitavastatin (1 mg to 4 mg) was 36.7 weeks (median 51.1 weeks). The mean age of the patients was 60.9 years (range; 18 years – 89 years) and 52% females. Approximately 93% of the patients were White 7% were Asian/Indian, 0.2% were African American and 0.3% were Hispanic and other. In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin-treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg). Adverse reactions reported in ≥ 2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks. Table 1. Adverse Reactions (≥ 2% and ≥ placebo) in Adult Patients with Primary Hyperlipidemia and Mixed Dyslipidemia in Studies up to 12 Weeks Adverse Reactions Placebo N=208 % Pitavastatin 1 mg N=309 % Pitavastatin 2 mg N=951 % Pitavastatin 4 mg N=1540 % Myalgia 1.4 1.9 2.8 3.1 Constipation 1.9 3.6 1.5 2.2 Diarrhea 1.9 2.6 1.5 1.9 Back pain 2.9 3.9 1.8 1.4 Pain in extremity 1.9 2.3 0.6 0.9 Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with pitavastatin. The following laboratory abnormalities have been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose. Adverse Reactions in Adult HIV-Infected Patients with Dyslipidemia In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either pitavastatin 4 mg once daily (n=126) or another statin (n=126). All patients were taking antiretroviral therapy (excluding darunavir) and had HIV-1 RNA less than 200 copies/mL and CD4 count greater than 200 cell/μL for at least 3 months prior to randomization. The safety profile of pitavastatin was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with pitavastatin had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with pitavastatin had at least one ALT value exceeding 3 times but less than 5 times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with pitavastatin, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline. Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavasta…