CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Pitavastatin is contraindicated in the following conditions: Known hypersensitivity to pitavastatin or any inactive ingredient in pitavastatin tablets. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with pitavastatin [see Adverse Reactions (6.1)] Concomitant use of cyclosporine [see Drug Interactions (7)]. Active liver disease including unexplained persistent elevations of hepatic transaminase levels [see Warnings And Precautions (5.3)]. Pregnancy [see Use In Specific Populations (8.1, 8.3)]. Lactation. It is not known if pitavastatin is present in human milk; however, another drug in this class passes into breast milk. Since HMG-CoA reductase inhibitors have the potential for serious adverse reactions in breastfed infants, females who require pitavastatin treatment should not breastfeed their infants [see Use In Specific Populations (8.2)]. Known hypersensitivity to pitavastatin or any inactive ingredient in pitavastatin tablets. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with pitavastatin [see Adverse Reactions (6.1)] . Concomitant use of cyclosporine [see Drug Interactions (7)]. Active liver disease including unexplained persistent elevations of hepatic transaminase levels [see Warnings And Precautions (5.3)]. Pregnancy [see Use In Specific Populations (8.1, 8.3)]. Lactation. It is not known if pitavastatin is present in human milk; however, another drug in this class passes into breast milk. Since HMG-CoA reductase inhibitors have the potential for serious adverse reactions in breastfed infants, females who require pitavastatin treatment should not breastfeed their infants [see Use In Specific Populations (8.2)]. Known hypersensitivity to product components (4, 6.1) Coadministration with cyclosporine (4, 7) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4, 5.3) Pregnancy (4, 8.1, 8.3) Lactation (4, 8.2). Known hypersensitivity to product components (4, 6.1). Coadministration with cyclosporine (4, 7). Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4, 5.3). Pregnancy (4, 8.1, 8.3). Lactation (4, 8.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at mg daily, there was an absence of drug-related tumors. In 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the mg daily maximum human dose. In 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed. Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested, which also elicited high levels of cytotoxicity. Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at mg daily based on AUC. Pitavastatin treatment in rabbits resulted in mortality in males and females given mg/kg/day (30-times clinical systemic exposure at mg daily based on AUC) and higher during fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.

ADVERSE REACTIONS SECTION.

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 Warning and Precautions (5.2)] Hepatic Dysfunction[see Warning and Precautions (5.3)] Increases in HbA1c and Fasting Serum Glucose Levels [see Warning and Precautions (5.4)]. Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)] Immune-Mediated Necrotizing Myopathy [see Warning and Precautions (5.2)] Hepatic Dysfunction[see Warning and Precautions (5.3)] Increases in HbA1c and Fasting Serum Glucose Levels [see Warning and Precautions (5.4)]. The most frequent adverse reactions (rate >= 2%) were myalgia, back pain, diarrhea, constipation and pain in extremity. (6)To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 and Mixed Dyslipidemia In 10 controlled clinical studies and subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia or mixed dyslipidemia were administered pitavastatin mg to mg daily. The mean continuous exposure of pitavastatin (1 mg to 4mg) was 36.7 weeks (median 51.1weeks). The mean age of the patients was 60.9 years (range; 18 years-89 years) and the gender distribution was 48% males and 52% females. Approximately 93% of the patients were Caucasian, 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 mg) and myalgia (0.5%on 4mg). Adverse reactions reported in>2% of patients in controlled clinical studies and at 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 upto 12 Weeks Adverse Reactions Placebo (n= 208) Pitavastatin mg (n=309) Pitavastatin mg (n=951) Pitavastatin mg (n=1540) Back Pain 2.9 3.9 1.8 1.4 Constipation 1.9 3.6 1.5 2.2 Diarrhea 1.9 2.6 1.5 1.9 Myalgia 1.4 1.9 2.8 3.1 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 DyslipidemiaIn double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either pitavastatin 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/uL for at least 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 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 3times but less than times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with pitavastatin, defined as confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than 2-fold increase from baseline. Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets.However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of pitavastatin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Gastrointestinal disorders: abdominal discomfort, abdominal pain, dyspepsia, nausea General disorders: asthenia, fatigue, malaise, dizziness Hepatobiliary disorders: hepatitis, jaundice, fatal and non-fatal hepatic failure Immune system disorders: immune-mediated necrotizing myopathy associated with statin use Metabolism and nutrition disorders: increases in HbA1c, fasting serum glucose levels Musculoskeletal and connective tissue disorders: muscle spasms, myopathy, rhabdomyolysis Nervous system disorders: hypoesthesia, peripheral neuropathy Psychiatric disorders: insomnia, depression. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of weeks). Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: interstitial lung disease.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Central Nervous System Toxicity CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at dose level of mg/kg/day (9 times clinical exposure at the maximum human dose of mg/day based on AUC comparisons).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, arate-limiting step in the biosynthetic pathway for cholesterol. As result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low density lipoproteins. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, pitavastatin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum dose of mg daily). 12.3 Pharmacokinetics. Absorption Pitavastatin peak plasma concentrations are achieved about hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single pitavastatin doses from mg to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon. Effect of Food Administration of pitavastatin with high fat meal (50% fat content) decreases pitavastatin Cmax by 43%but does not significantly reduce pitavastatin AUC.DistributionPitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal. EliminationMetabolism The principal route of pitavastatin metabolism is glucuronidation vialiveruridine 5-diphosphateglucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. Pitavastatin is marginally metabolized by CYP2C9 and to lesser extent by CYP2C8.The major metabolite in human plasma is the lactone, which is formed via an ester-type pitavastatin glucuronide conjugate by UGTs (UGT1A3 andUGT2B7). ExcretionA mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas mean of 79% of the dose was excreted in feces within days. The mean plasma elimination half-life is approximately 12 hours. Specific Populations Racial or Ethnic Groups In pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC. Male and Female Patients In pharmacokinetic study, which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. Geriatric Patients In pharmacokinetic study which compared healthy young and geriatric (>=65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the geriatric patients [see Use in Specific Populations (8.5)] Pediatric Patients Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.Patients with Renal ImpairmentIn patients with moderate renal impairment (estimated glomerular filtration rate of 30 to 59 mL/min/ 1.73 m2) and end stage renal disease receiving hemodialysis, pitavastatin AUC0-inf is 102% and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax is 60% and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33% and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively [see Use in Specific Populations (8.6)].In another pharmacokinetic study, patients with severe renal impairment (estimated glomerular filtration rate 15 to 29 mL/min/1.73 m2) not receiving hemodialysis were administered single dose of pitavastatin mg. The AUC0-inf and the Cmax were 36% and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6% [see Use in Specific Populations (8.6)]. The effect of mild renal impairment on pitavastatin exposure has not been studied. Patients with Hepatic ImpairmentThe disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. Pitavastatin Cmax and AUCinf in patients with moderate hepatic impairment (Child-Pugh disease) was 2.7-fold and 3.8-fold higher, respectively as compared to healthy volunteers. In patients with mild hepatic impairment (Child-Pugh disease), pitavastatin Cmax and AUCinf were 30% and 60% higher as compared to healthy volunteers. Mean pitavastatin half-life for moderate hepatic impairment, mild hepatic impairment, and healthyvolunteerswere15, 10, and hours, respectively [see Contraindications (4), Warnings and Precautions (5.3)].Drug Interaction Studies Warfarin The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of pitavastatin mg daily. Table presents the effect of coadministered drugs on pitavastatin systemic exposure:Table 3. Effect of Coadministered Drugs on Pitavastatin Systemic Exposure Coadministered drug Dosage regimen Change in AUC Change in Cmax Cyclosporine Pitavastatin mg QD for days cyclosporine mg/kg on Day 4.6 fold+ 6.6 fold Erythromycin Pitavastatin mg single dose on Day + erythromycin 500 mg times daily for days 2.8 fold 3.6 fold Rifampin Pitavastatin mg QD rifampin 600 mg QD for days 29% 2.0 fold Atazanavir Pitavastatin mg QD atazanavir 300 mg daily for days 31% 60% Darunavir/Ritonavir Pitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 26% 4% Lopinavir/Ritonavir Pitavastatin mg QD on Days 1-5 and 20 24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 20% % Gemfibrozil Pitavastatin mg QD gemfibrozil 600 mg BID for days 45% 31% Fenofibrate Pitavastatin mg QD fenofibrate 160 mg QD for days 18% 11% Ezetimibe Pitavastatin mg QD ezetimibe 10 mg for days 2% 0.2% Enalapril Pitavastatin mg QD enalapril 20 mg daily for days 6% 7% Digoxin Pitavastatin mg QD digoxin 0.25 mg for days 4% 9% Diltiazem LA Pitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 10% 15% Grapefruit Juice Pitavastatin mg single dose on Day + grapefruit juice for days 15% 12% Itraconazole Pitavastatin mg single dose on Day + itraconazole 200 mg daily for days 23% 22% Data presented as x-fold change represent the ratio between coadministration and pitavastatin alone (i.e., 1-fold no change). Data presented as change represent difference relative to pitavastatin alone (i.e., 0% no change). Considered clinically significant [see Dosage And Administration (2.4), Drug Interactions (7)] BID twice daily; QD once daily; LA Long ActingTable presents the effect of pitavastatin coadministration on systemic exposure of other drugs:Table 4. Effect of Pitavastatin Coadministration on Systemic Exposure to Other Drugs Coadministered drug Dosage regimen Change in AUC Change in Cmax Atazanavir Pitavastatin mg QD atazanavir 300 mg daily for days 6% 13% Darunavir Pitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 3% 6% Lopinavir Pitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 9% 7% Ritonavir Pitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 11% 11% Ritonavir Pitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 8% 2% Enalapril Pitavastatin mg QD enalapril 20 mg daily for days Enalapril 12% 12% Enalaprilat 1% 1% Warfarin Individualized maintenance dose of warfarin (2 -7 mg) for days pitavastatin mg QD for days R-warfarin 7% 3% S-warfarin 6% 3% Ezetimibe Pitavastatin mg QD ezetimibe 10 mg for days 9% 2% Digoxin Pitavastatin mg QD digoxin 0.25 mg for days 3% 4% Diltiazem LA Pitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 2% 7% Rifampin Pitavastatin mg QD rifampin 600 mg QD for days 15% 18% Data presented as change represent difference relative to the investigated drug alone (i.e., 0% no change). BID twice daily; QD once daily; LA Long Acting.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Primary Hyperlipidemia or Mixed Dyslipidemia in Adult Patients. Active-Controlled Study with Atorvastatin (Study 301) Pitavastatin was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 817 adult patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered 6 to 8-week wash-out/dietary lead-in period and then were randomized to 12-week treatment with either pitavastatin or atorvastatin (Table 5). Non-inferiority of pitavastatin to given dose of atorvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. Lipid results are shown in Table 5. For the percent change from baseline to endpoint in LDL-C, pitavastatin was non-inferior to atorvastatin for the two pairwise comparisons: pitavastatin mg vs. atorvastatin 10 mg and pitavastatin mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively. Table 5. Lipid Response by Dose of Pitavastatin and Atorvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 301 (Mean Change from Baseline at Week 12) Treatment LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin mg daily 315 -38 -30 -28 -14 -35 Pitavastatin mg daily 298 -45 -35 -32 -19 -41 Atorvastatin 10 mg daily 102 -38 -29 -28 -18 -35 Atorvastatin 20 mg daily 102 -44 -36 -33 -22 -41 Active-Controlled Study with Simvastatin (Study 302) Pitavastatin was compared with Simvastatin Tablets (referred to as simvastatin) in randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 843 adult patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered 6- to 8-week wash-out/dietary lead-in period and then were randomized to 12 week treatment with either pitavastatin or simvastatin (Table 6). Non-inferiority of pitavastatin to given dose of simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. Lipid results are shown in Table 6. For the percent change from baseline to endpoint in LDL-C, pitavastatin was non-inferior to simvastatin for the two pairwise comparisons: pitavastatin mg vs. simvastatin 20 mg and pitavastatin mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.Table 6. Lipid Response by Dose of Pitavastatin and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 302 (Mean Change from Baseline at Week 12) Treatment LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin mg daily 307 -39 -30 -28 -16 -36 Pitavastatin mg daily 319 -44 -35 -32 -17 -41 Simvastatin 20 mg daily 107 -35 -27 -25 -16 -32 Simvastatin 40 mg daily 110 -43 -34 -31 -16 -39 Active-Controlled Study with Pravastatin in Geriatric Patients (Study-306) Pitavastatin was compared with Pravastatin Sodium Tablets (referred to as pravastatin) in randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority study of 942 geriatric patients (>=65 years) with primary hyperlipidemia or mixed dyslipidemia. Patients entered 6-to 8-week wash-out/dietary lead-in period, and then were randomized to once daily dose of pitavastatin or pravastatin for 12 weeks (Table 7). Non-inferiority of pitavastatin to given dose of pravastatin was assumed if the lower bound of the 95% CI for the treatment difference was greater than -6% for the mean percent change in LDL-C. Lipid results are shown in Table 7. Pitavastatin significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: Pitavastatin mg vs. pravastatin 10 mg, pitavastatin mg vs. pravastatin 20 mg and pitavastatin mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.Table 7. Lipid Response by Dose of Pitavastatin and Pravastatin in Geriatric Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 306 (Mean Change from Baseline at Week 12) Treatment LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin mg daily 207 -31 -25 -22 -13 -29 Pitavastatin mg daily 224 -39 -31 -27 -15 -36 Pitavastatin mg daily 210 -44 -37 -31 -22 -41 Pravastatin 10 mg daily 103 -22 -17 -15 -5 -20 Pravastatin 20 mg daily 96 -29 -22 -21 -11 -1 -27 Pravastatin 40 mg daily 102 -34 -28 -24 -15 -32 Active-Controlled Study with Simvastatin in Patients with >= Risk Factors for Coronary Heart Disease (Study 304)Pitavastatin was compared with Simvastatin Tablets (referred to as simvastatin) in randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 351 adult patients with primary hyperlipidemia or mixed dyslipidemia with >=2 risk factors for coronary heart disease. After 6- to 8-week wash-out/dietary lead-in period, patients were randomized to 12-week treatment with either pitavastatin or simvastatin (Table 8). Non-inferiority of pitavastatin to simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. Lipid results are shown in Table 8. Pitavastatin mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference (95% CI) was 0% (-2%, 3%).Table 8. Lipid Response by Dose of Pitavastatin and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia with >=2 Risk Factors for Coronary Heart Disease in Study 304 (Mean Change from Baseline at Week 12) Treatment LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin mg daily 233 -44 -34 -31 -20 -40 Simvastatin 40 mg daily 118 -44 -34 -31 -15 -39 Active-Controlled Study with Atorvastatin in Patients with Type Diabetes Mellitus (Study 305)Pitavastatin was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority study of 410 adult patients with type diabetes mellitus and mixed dyslipidemia. Patients entered 6-to 8-week washout/dietary lead-in period and were randomized to once daily dose of pitavastatin or atorvastatin for 12 weeks. Non-inferiority of pitavastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. Lipid results are shown in Table 9. The treatment difference (95% CI) for LDL-C percent change from baseline was-2% (-6.2%, 1.5%). The two treatment groups were not statistically different on LDL-C. However, the lower limit of the CI was -6.2%, slightly exceeding the-6% non-inferiority limit. The study failed to demonstrate that pitavastatin was not significantly different than atorvastatin in lowering LDL-C in patients with type diabetes mellitus and mixed dyslipidemia. Table 9. Lipid Response by Dose of Pitavastatin and Atorvastatin in Adult Patients with Type Diabetes Mellitus and Mixed Dyslipidemia in Study 305 (Mean Change from Baseline at Week 12) Treatment LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin mg daily 274 -41 -32 -28 -20 -36 Atorvastatin 20 mg daily 136 -43 -34 -32 -27 -40 The treatment differences in efficacy in LDL-C change from baseline between pitavastatin and active controls (i.e., atorvastatin, simvastatin, or pravastatin) in the in the active-controlled studies described above are summarized in Figure 1. NL=non-inferiority limit.Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.. Image.

DESCRIPTION SECTION.

11 DESCRIPTION. Pitavastatin tablets for oral use is an HMG-CoA reductase inhibitor.The chemical name for pitavastatin is (+) monocalcium bis (3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate. The structural formula is:The empirical formula for pitavastatin is C50H46CaF2N2O8 and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is sparingly soluble in tetrahydrofuran. Pitavastatin is hygroscopic and slightly unstable in light. Each film-coated tablet of pitavastatin contains mg, mg, or mg of pitavastatin, which is equivalent to 1.045 mg, 2.09 mg, or 4.18 mg, respectively, of pitavastatin calcium and, the following inactive ingredients: hypromellose, lactose monohydrate, low substituted hydroxypropylcellulose, magnesium aluminometasilicate and magnesium stearate. The film coating contains the following inactive ingredients: colloidal anhydrous silica, hypromellose, titanium dioxide and triethyl citrate. Image.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Take pitavastatin tablets orally once daily with or without food at the same time each day (2.1).Individualize the dose of pitavastatin tablets according to patient characteristics, goal of therapy, and response (2.1).After initiation or upon titration, analyze lipid levels after weeks and adjust the dosage accordingly (2.1).The recommended starting pitavastatin tablets dosage is mg once daily (2.2).The maximum recommended dosage is pitavastatin tablets mg once daily (2.2).The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 and 15 to 29 mL/min/1.73 m2, respectively) as well as end-stage renal disease on hemodialysis is pitavastatin tablets mg once daily and the maximum dose is mg once daily (2.3)There are pitavastatin tablets dosage adjustments due to drug interactions for:Patients taking erythromycin, do not exceed mg once daily (2.4).Patients taking rifampin, do not exceed mg once daily (2.4). Take pitavastatin tablets orally once daily with or without food at the same time each day (2.1).. Individualize the dose of pitavastatin tablets according to patient characteristics, goal of therapy, and response (2.1).. After initiation or upon titration, analyze lipid levels after weeks and adjust the dosage accordingly (2.1).. The recommended starting pitavastatin tablets dosage is mg once daily (2.2).. The maximum recommended dosage is pitavastatin tablets mg once daily (2.2).. The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 and 15 to 29 mL/min/1.73 m2, respectively) as well as end-stage renal disease on hemodialysis is pitavastatin tablets mg once daily and the maximum dose is mg once daily (2.3). There are pitavastatin tablets dosage adjustments due to drug interactions for:Patients taking erythromycin, do not exceed mg once daily (2.4).Patients taking rifampin, do not exceed mg once daily (2.4). Patients taking erythromycin, do not exceed mg once daily (2.4).. Patients taking rifampin, do not exceed mg once daily (2.4).. 2.1 General Dosage and Administration Information. Take pitavastatin tablets orally once daily with or without food at the same time each day.Individualize the dose of pitavastatin according to patient characteristics, goal of therapy, and response.After initiation or upon titration of pitavastatin, analyse lipid levels after weeks and adjust the dosage accordingly.. Take pitavastatin tablets orally once daily with or without food at the same time each day.. Individualize the dose of pitavastatin according to patient characteristics, goal of therapy, and response.. After initiation or upon titration of pitavastatin, analyse lipid levels after weeks and adjust the dosage accordingly.. 2.2 Recommended Dosage for Adults. The recommended starting pitavastatin tablets dosage is mg once daily.The maximum recommended dosage is pitavastatin tablets mg once daily [see Warnings and Precautions (5.1)] .. The recommended starting pitavastatin tablets dosage is mg once daily.. The maximum recommended dosage is pitavastatin tablets mg once daily [see Warnings and Precautions (5.1)] .. 2.3 Recommended Dosage in Patients with Renal Impairment. The recommended starting dose for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 mL/minute/1.73 m2and 15 to 29 mL/minute/1.73 m2, respectively) and patients with end-stage renal disease receiving hemodialysis is pitavastatin tablets mg once daily.The maximum recommended dose for these patients is pitavastatin tablets mg once daily [see Use in Specific Populations (8.6)] .. The recommended starting dose for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 mL/minute/1.73 m2and 15 to 29 mL/minute/1.73 m2, respectively) and patients with end-stage renal disease receiving hemodialysis is pitavastatin tablets mg once daily.. The maximum recommended dose for these patients is pitavastatin tablets mg once daily [see Use in Specific Populations (8.6)] .. 2.4 Pitavastatin Tablets Dosage Adjustments Due to Drug Interactions. In patients taking erythromycin, do not exceed pitavastatin tablets 1mg once daily [see Drug Interactions (7)] .In patients taking rifampin, do not exceed pitavastatin tablets mg once daily [see Drug Interactions (7)] .Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.. In patients taking erythromycin, do not exceed pitavastatin tablets 1mg once daily [see Drug Interactions (7)] .. In patients taking rifampin, do not exceed pitavastatin tablets mg once daily [see Drug Interactions (7)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: mg: White to off-white, round, film-coated tablets, debossed with LU on one side and Y61 on the other side. mg: White to off-white, round, film-coated tablets, debossed with LU on one side and Y62 on the other side. mg: White to off-white, round, film-coated tablets, debossed with LU on one side and Y63 on the other side.. mg: White to off-white, round, film-coated tablets, debossed with LU on one side and Y61 on the other side.. mg: White to off-white, round, film-coated tablets, debossed with LU on one side and Y62 on the other side.. mg: White to off-white, round, film-coated tablets, debossed with LU on one side and Y63 on the other side.. Tablets: mg, mg, and mg (3). Tablets: mg, mg, and mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pitavastatin Table includes list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with pitavastatin 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 Pitavastatin Cyclosporine Clinical Impact: Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention: Concomitant use of cyclosporine with pitavastatin 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 pitavastatin. Erythromycin Clinical Impact: Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention: In patients taking erythromycin, do not exceed pitavastatin 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 pitavastatin 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 pitavastatin 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 pitavastatin 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 pitavastatin. Gemfibrozil: Avoid concomitant use with pitavastatin (7) Fibrates: Consider if the benefit of using fibrates concomitantly with pitavastatin outweighs the increased risk of myopathy and rhabdomyolysis (7) Niacin: Consider if the benefit of using lipid-modifying doses (>1 g/day) of niacin concomitantly with pitavastatin outweighs the increased risk of myopathy and rhabdomyolysis (7) Colchicine: Consider the risk/benefit of concomitant use with pitavastatin (7). Gemfibrozil: Avoid concomitant use with pitavastatin (7). Fibrates: Consider if the benefit of using fibrates concomitantly with pitavastatin outweighs the increased risk of myopathy and rhabdomyolysis (7). Niacin: Consider if the benefit of using lipid-modifying doses (>1 g/day) of niacin concomitantly with pitavastatin outweighs the increased risk of myopathy and rhabdomyolysis (7). Colchicine: Consider the risk/benefit of concomitant use with pitavastatin (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. In controlled clinical studies, 1,209(43%) patients were 65years and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Advanced age (>=65 years) is risk factor for myopathy and rhabdomyolysis. In general, dose selection fora geriatric patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy [see Warnings and Precautions (5.1)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Pitavastatin tablets are supplied as follows: Tablet Strength Package Size Tablet Description NDC mg Bottle of 90 tablets with child-resistant closure. White to off-white, round, film-coated tablets debossed with LU on one side and Y61 on the other side. NDC 68180-735-09 Bottle of 500 tablets with non-child-resistant closure. NDC 68180-735-02 mg Bottle of 90 tablets with child-resistant closure. White to off-white, round, film-coated tablets debossed with LU on one side and Y62 on the other side. NDC 68180-736-09 Bottle of 500 tablets with non-child-resistant closure. NDC 68180-736-02 mg Bottle of 90 tablets with child-resistant closure. White to off-white, round, film-coated tablets debossed with LU on one side and Y63 on the other side. NDC 68180-737-09 Bottle of 500 tablets with non-child-resistant closure. NDC 68180-737-02 Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86 F) [see USP Controlled Room Temperature]. Protect from light.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Pitavastatin is indicated as an adjunctive therapy to diet in:Adult patients with primary hyperlipidemia or mixed dyslipidemia to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C).Limitations of Use The effect of pitavastatin on cardiovascular morbidity and mortality has not been determined.Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.. Adult patients with primary hyperlipidemia or mixed dyslipidemia to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C).. The effect of pitavastatin on cardiovascular morbidity and mortality has not been determined.. Pitavastatin is HMG-CoA reductase inhibitor indicated as an adjunctive therapy to diet in: Adult patients with primary hyperlipidemia or mixed dyslipidemia to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) (1).Limitations of Use: The effect of pitavastatin on cardiovascular morbidity and mortality has not been determined.. Adult patients with primary hyperlipidemia or mixed dyslipidemia to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) (1).. The effect of pitavastatin on cardiovascular morbidity and mortality has not been determined.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. The patient should be informed of the following: Myopathy and Rhabdomyolysis Advise patients that pitavastatin may cause myopathy and rhabdomyolysis. Inform patients that the risk is increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1)]. Hepatic Dysfunction Inform patients that pitavastatin may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with pitavastatin. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)]. Embryo-fetal Toxicity Advise females of reproductive potential of the potential risk to fetus, to use effective contraception during treatment and to inform their healthcare professional of known or suspected pregnancy [see Contraindications (4), Use in Specific Populations (8.1, 8.3)]. Lactation Advise women not to breastfeed during treatment with pitavastatin [see Contraindications (4), Use in Specific Populations (8.2)]. Liver Enzymes It is recommended that liver enzyme tests be checked before the initiation of pitavastatin and if signs or symptoms of liver injury occur. All patients treated with pitavastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.Manufactured for:Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United StatesManufactured by:Lupin LimitedPithampur (M.P.) 454 775IndiaNovember 2019 ID: 242172.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, arate-limiting step in the biosynthetic pathway for cholesterol. As result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low density lipoproteins.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at mg daily, there was an absence of drug-related tumors. In 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the mg daily maximum human dose. In 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed. Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested, which also elicited high levels of cytotoxicity. Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at mg daily based on AUC. Pitavastatin treatment in rabbits resulted in mortality in males and females given mg/kg/day (30-times clinical systemic exposure at mg daily based on AUC) and higher during fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed. 13.2 Animal Toxicology and/or Pharmacology. Central Nervous System Toxicity CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at dose level of mg/kg/day (9 times clinical exposure at the maximum human dose of mg/day based on AUC comparisons).

OVERDOSAGE SECTION.

10 OVERDOSAGE. No specific treatment for pitavastatin overdose is known. Contact Poison Control (1-800-222-1222) for latest recommendations. Hemodialysis is unlikely to be of benefit due to high protein binding ratio of pitavastatin.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Pitavastatin Tablets, mgRx OnlyNDC 68180-735-0990 TabletsPitavastatin Tablets, mgRx OnlyNDC 68180-736-0990 TabletsPitavastatin Tablets, mgRx OnlyNDC 68180-737-0990 Tablets. mg 90 Tablets. mg 90 Tablets. mg 90 Tablets.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of pitavastatin have not been established in pediatric patients younger than years of age with heterozygous familial hypercholesterolemia (HeFH) or in pediatric patients with other types of hyperlipidemia (other than HeFH). Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, pitavastatin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum dose of mg daily).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Pitavastatin peak plasma concentrations are achieved about hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single pitavastatin doses from mg to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon. Effect of Food Administration of pitavastatin with high fat meal (50% fat content) decreases pitavastatin Cmax by 43%but does not significantly reduce pitavastatin AUC.DistributionPitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal. EliminationMetabolism The principal route of pitavastatin metabolism is glucuronidation vialiveruridine 5-diphosphateglucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. Pitavastatin is marginally metabolized by CYP2C9 and to lesser extent by CYP2C8.The major metabolite in human plasma is the lactone, which is formed via an ester-type pitavastatin glucuronide conjugate by UGTs (UGT1A3 andUGT2B7). ExcretionA mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas mean of 79% of the dose was excreted in feces within days. The mean plasma elimination half-life is approximately 12 hours. Specific Populations Racial or Ethnic Groups In pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC. Male and Female Patients In pharmacokinetic study, which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. Geriatric Patients In pharmacokinetic study which compared healthy young and geriatric (>=65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the geriatric patients [see Use in Specific Populations (8.5)] Pediatric Patients Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.Patients with Renal ImpairmentIn patients with moderate renal impairment (estimated glomerular filtration rate of 30 to 59 mL/min/ 1.73 m2) and end stage renal disease receiving hemodialysis, pitavastatin AUC0-inf is 102% and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax is 60% and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33% and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively [see Use in Specific Populations (8.6)].In another pharmacokinetic study, patients with severe renal impairment (estimated glomerular filtration rate 15 to 29 mL/min/1.73 m2) not receiving hemodialysis were administered single dose of pitavastatin mg. The AUC0-inf and the Cmax were 36% and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6% [see Use in Specific Populations (8.6)]. The effect of mild renal impairment on pitavastatin exposure has not been studied. Patients with Hepatic ImpairmentThe disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. Pitavastatin Cmax and AUCinf in patients with moderate hepatic impairment (Child-Pugh disease) was 2.7-fold and 3.8-fold higher, respectively as compared to healthy volunteers. In patients with mild hepatic impairment (Child-Pugh disease), pitavastatin Cmax and AUCinf were 30% and 60% higher as compared to healthy volunteers. Mean pitavastatin half-life for moderate hepatic impairment, mild hepatic impairment, and healthyvolunteerswere15, 10, and hours, respectively [see Contraindications (4), Warnings and Precautions (5.3)].Drug Interaction Studies Warfarin The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of pitavastatin mg daily. Table presents the effect of coadministered drugs on pitavastatin systemic exposure:Table 3. Effect of Coadministered Drugs on Pitavastatin Systemic Exposure Coadministered drug Dosage regimen Change in AUC Change in Cmax Cyclosporine Pitavastatin mg QD for days cyclosporine mg/kg on Day 4.6 fold+ 6.6 fold Erythromycin Pitavastatin mg single dose on Day + erythromycin 500 mg times daily for days 2.8 fold 3.6 fold Rifampin Pitavastatin mg QD rifampin 600 mg QD for days 29% 2.0 fold Atazanavir Pitavastatin mg QD atazanavir 300 mg daily for days 31% 60% Darunavir/Ritonavir Pitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 26% 4% Lopinavir/Ritonavir Pitavastatin mg QD on Days 1-5 and 20 24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 20% % Gemfibrozil Pitavastatin mg QD gemfibrozil 600 mg BID for days 45% 31% Fenofibrate Pitavastatin mg QD fenofibrate 160 mg QD for days 18% 11% Ezetimibe Pitavastatin mg QD ezetimibe 10 mg for days 2% 0.2% Enalapril Pitavastatin mg QD enalapril 20 mg daily for days 6% 7% Digoxin Pitavastatin mg QD digoxin 0.25 mg for days 4% 9% Diltiazem LA Pitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 10% 15% Grapefruit Juice Pitavastatin mg single dose on Day + grapefruit juice for days 15% 12% Itraconazole Pitavastatin mg single dose on Day + itraconazole 200 mg daily for days 23% 22% Data presented as x-fold change represent the ratio between coadministration and pitavastatin alone (i.e., 1-fold no change). Data presented as change represent difference relative to pitavastatin alone (i.e., 0% no change). Considered clinically significant [see Dosage And Administration (2.4), Drug Interactions (7)] BID twice daily; QD once daily; LA Long ActingTable presents the effect of pitavastatin coadministration on systemic exposure of other drugs:Table 4. Effect of Pitavastatin Coadministration on Systemic Exposure to Other Drugs Coadministered drug Dosage regimen Change in AUC Change in Cmax Atazanavir Pitavastatin mg QD atazanavir 300 mg daily for days 6% 13% Darunavir Pitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 3% 6% Lopinavir Pitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 9% 7% Ritonavir Pitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 11% 11% Ritonavir Pitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 8% 2% Enalapril Pitavastatin mg QD enalapril 20 mg daily for days Enalapril 12% 12% Enalaprilat 1% 1% Warfarin Individualized maintenance dose of warfarin (2 -7 mg) for days pitavastatin mg QD for days R-warfarin 7% 3% S-warfarin 6% 3% Ezetimibe Pitavastatin mg QD ezetimibe 10 mg for days 9% 2% Digoxin Pitavastatin mg QD digoxin 0.25 mg for days 3% 4% Diltiazem LA Pitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 2% 7% Rifampin Pitavastatin mg QD rifampin 600 mg QD for days 15% 18% Data presented as change represent difference relative to the investigated drug alone (i.e., 0% no change). BID twice daily; QD once daily; LA Long Acting.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPitavastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with pitavastatin during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, pitavastatin may cause fetal harm when administered to pregnant women. Pitavastatin should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of pitavastatin are insufficient to determine drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed when pregnant rats and rabbits were orally administered pitavastatin during organogenesis at exposures which were 22 and times, respectively, the maximum recommended human dose (MRHD) [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. 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.DataHuman DataLimited published data on pitavastatin have not reported drug-associated risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate to exclude greater than or equal to 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.Animal DataReproductive toxicity studies have shown that pitavastatin crosses the placenta in rats and is found in fetal tissues at <= 36% of maternal plasma concentrations following single dose of mg/kg/day during gestation. Embryo-fetal developmental studies were conducted in pregnant rats treated with 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. No adverse effects were observed at mg/kg/day, systemic exposures 22 times human systemic exposure at mg/day based on AUC. Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at mg/day based on AUC).In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at >=0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups (0.1 mg/kg/day represents approximately time human systemic exposure at mg/day dose based on AUC).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Females of Reproductive Potential Advise females to use effective contraception during treatment. (8.3)Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.. Females of Reproductive Potential Advise females to use effective contraception during treatment. (8.3). 8.1 Pregnancy. Risk SummaryPitavastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with pitavastatin during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, pitavastatin may cause fetal harm when administered to pregnant women. Pitavastatin should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of pitavastatin are insufficient to determine drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed when pregnant rats and rabbits were orally administered pitavastatin during organogenesis at exposures which were 22 and times, respectively, the maximum recommended human dose (MRHD) [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. 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.DataHuman DataLimited published data on pitavastatin have not reported drug-associated risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate to exclude greater than or equal to 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.Animal DataReproductive toxicity studies have shown that pitavastatin crosses the placenta in rats and is found in fetal tissues at <= 36% of maternal plasma concentrations following single dose of mg/kg/day during gestation. Embryo-fetal developmental studies were conducted in pregnant rats treated with 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. No adverse effects were observed at mg/kg/day, systemic exposures 22 times human systemic exposure at mg/day based on AUC. Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at mg/day based on AUC).In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at >=0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups (0.1 mg/kg/day represents approximately time human systemic exposure at mg/day dose based on AUC). 8.2 Lactation. Risk SummaryPitavastatin is contraindicated during breastfeeding [see Contraindications (4.)]. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Because of the potential for serious adverse reactions in breastfed infant, advise patients that breastfeeding is not recommended during treatment with pitavastatin.. 8.3 Females and Males of Reproductive Potential. ContraceptionFemalesPitavastatin may cause fetal harm when administered to pregnant woman [see Use In Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with pitavastatin.. 8.4 Pediatric Use. The safety and effectiveness of pitavastatin have not been established in pediatric patients younger than years of age with heterozygous familial hypercholesterolemia (HeFH) or in pediatric patients with other types of hyperlipidemia (other than HeFH). Pediatric use information is approved for Kowa Co Ltds LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltds marketing exclusivity rights, this drug product is not labeled with that information.. 8.5 Geriatric Use. In controlled clinical studies, 1,209(43%) patients were 65years and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Advanced age (>=65 years) is risk factor for myopathy and rhabdomyolysis. In general, dose selection fora geriatric patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment. Renal impairment is risk factor for myopathy and rhabdomyolysis. Due to the risk of myopathy, dosage modification of pitavastatin is recommended for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 -59 mL/min/1.73 m2and15 -29 mL/min/1.73 m2, respectively), as well as end-stage renal disease receiving hemodialysis. [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment. Pitavastatin is contraindicated in patients with active liver disease including unexplained persistent elevations of hepatic transaminase levels [see Contraindications (4), Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myopathy and Rhabdomyolysis: Risk factors include age 65 and greater, renal impairment, inadequately treated hypothyroidism, and higher doses of pitavastatin. Discontinue pitavastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue pitavastatin 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 pitavastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever (5.1). Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents (5.2). Hepatic Dysfunction Increases in serum transaminases can occur. Rare postmarketing reports of fatal and non-fatal hepatic failure have occurred. Consider liver enzyme testing before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pitavastatin (5.3) Increases in HbA1c and Fasting Serum Glucose Levels: Have been reported with statins, including pitavastatin. Optimize lifestyle measures, including regular exercise, maintaining healthy body weight, and making healthy food choices. (5.4). Myopathy and Rhabdomyolysis: Risk factors include age 65 and greater, renal impairment, inadequately treated hypothyroidism, and higher doses of pitavastatin. Discontinue pitavastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue pitavastatin 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 pitavastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever (5.1).. Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents (5.2).. Hepatic Dysfunction Increases in serum transaminases can occur. Rare postmarketing reports of fatal and non-fatal hepatic failure have occurred. Consider liver enzyme testing before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pitavastatin (5.3). Increases in HbA1c and Fasting Serum Glucose Levels: Have been reported with statins, including pitavastatin. Optimize lifestyle measures, including regular exercise, maintaining healthy body weight, and making healthy food choices. (5.4). 5.1 Myopathy and Rhabdomyolysis. Pitavastatin may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as result of rhabdomyolysis with statin use, 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, and higher pitavastatin dosage. Dosages of pitavastatin greater than mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of pitavastatin is mg once daily [see Dosage and Administration (2.2)]. Steps to Prevent or Reduce the Risk of Myopathy and RhabdomyolysisPitavastatin 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 pitavastatin may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1grams/day), fibrates, and colchicine [see Drug Interactions (7)]. Discontinue pitavastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if pitavastatin is discontinued. Temporarily discontinue pitavastatin 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 pitavastatin 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. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. 5.3 Hepatic Dysfunction. Increases in serum transaminases have been reported with pitavastatin [see Adverse Reactions (6)]. In most cases, the elevations were transient and either resolved or improved on continued therapy or after brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. Patients who consume substantial quantities of alcohol and/or have history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before the initiation of pitavastatin and thereafter, when clinically indicated. Pitavastatin is contraindicated in patients with active liver disease including unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pitavastatin. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels. Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pitavastatin. Optimize lifestyle measures, including regular exercise, maintaining healthy body weight, and making healthy food choices.