DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with LIVALO 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 LIVALOCyclosporineClinical Impact:Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention:Concomitant use of cyclosporine with LIVALO is contraindicated [see Contraindications (4)]. GemfibrozilClinical Impact:Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with statins, including LIVALO.Intervention:Avoid concomitant use of gemfibrozil with LIVALO.ErythromycinClinical Impact:Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention:In patients taking erythromycin, do not exceed LIVALO mg once daily [see Dosage and Administration (2.4)]. RifampinClinical Impact:Rifampin significantly increases peak pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Intervention:In patients taking rifampin, do not exceed LIVALO 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 LIVALO.Intervention:Consider if the benefit of using fibrates concomitantly with LIVALO outweighs the increased risk of myopathy and rhabdomyolysis.NiacinClinical Impact:The risk of myopathy and rhabdomyolysis may be increased with concomitant use of lipid-modifying doses (>=1 g/day) of niacin with LIVALO.Intervention:Consider if the benefit of using lipid-modifying doses (>=1 g/day) of niacin concomitantly with LIVALO outweighs the increased risk of myopathy and rhabdomyolysis.ColchicineClinical Impact:Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with statins, including LIVALO.Intervention:Consider the risk/benefit of concomitant use of colchicine with LIVALO.. See full prescribing information for details regarding concomitant use of LIVALO with other drugs that increase the risk of myopathy and rhabdomyolysis. (2.4, 7).

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, constipation, diarrhea, back pain, and pain in extremity. (6)To report SUSPECTED ADVERSE REACTIONS, contact Kowa Pharmaceuticals America, Inc. at 1-877-334-3464 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 HyperlipidemiaIn 10 controlled clinical studies and subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia were administered LIVALO mg to mg daily. The mean continuous exposure of pitavastatin (1 mg to 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% were 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 LIVALO-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 mg).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 Adults with Primary Hyperlipidemia in Studies up to 12 WeeksAdverse ReactionsPlacebo(n= 208)%LIVALO mg(n=309)%LIVALO mg(n=951)%LIVALO mg(n=1540)%Myalgia1.41.92.83.1Constipation1.93.61.52.2Diarrhea1.92.61.51.9Back pain2.93.91.81.4Pain in extremity1.92.30.60.9Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis.Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with LIVALO.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 LIVALO 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 LIVALO was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with LIVALO had peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with LIVALO had at least one ALT value exceeding times but less than times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with LIVALO, defined as confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than 2-fold increase from baseline.. Adverse Reactions in Pediatric Patients Aged Years and Older with HeFHIn 12-week, double-blind, placebo-controlled trial of LIVALO mg, mg, and mg once daily in 82 pediatric patients years to 16 years of age with HeFH and 52-week open-label trial in 85 pediatric patients with HeFH, the safety profile was similar to that observed in the adult population.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of LIVALO. 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: angioedema, 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. There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or different statin was administered. 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). Psychiatric disorders: insomnia, depression Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: interstitial lung disease Skin and subcutaneous tissue disorders: lichen planus. 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: angioedema, 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. There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or different statin was administered. 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).. Psychiatric disorders: insomnia, depression. Reproductive system and breast disorders: erectile dysfunction. Respiratory, thoracic and mediastinal disorders: interstitial lung disease. Skin and subcutaneous tissue disorders: lichen planus.

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.

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, rate-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, LIVALO 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. AbsorptionPitavastatin peak plasma concentrations are achieved about hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single LIVALO 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 FoodAdministration of LIVALO 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. Elimination. MetabolismThe principal route of pitavastatin metabolism is glucuronidation via liver uridine 5-diphosphate glucuronosyltransferase (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 and UGT2B7). 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. 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 (8.4)]. Pediatric PatientsA 12-week study in pediatric patients to 16 years of age treated with pitavastatin mg, mg and mg administered once daily, showed dose-dependent increase in pitavastatin plasma concentrations at trough (for mg and mg doses) and hour post dose. dose-dependent increase in pitavastatin lactone plasma concentrations was observed at trough and hour post dose.. Male and Female PatientsIn pharmacokinetic study, which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. Racial or Ethnic GroupsIn pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of White healthy volunteers. In pharmacokinetic comparison between White volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.. Patients with Renal ImpairmentIn patients with moderate renal impairment (estimated glomerular filtration rate of 30 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 (8.5)]. In another pharmacokinetic study, patients with severe renal impairment (estimated glomerular filtration rate 15 29 mL/min/1.73 m2) not receiving hemodialysis were administered single dose of LIVALO 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 (8.5)].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 healthy volunteers were 15, 10, and hours, respectively [see Contraindications (4), Warnings and Precautions (5.3)]. Drug Interaction Studies. WarfarinThe steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of LIVALO mg daily.Table presents the effect of coadministered drugs on pitavastatin systemic exposure:Table 3. Effect of Coadministered Drugs on Pitavastatin Systemic ExposureCoadministered drugDosage regimenChange in AUCData 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). Change in Cmax BID twice daily; QD once daily; LA Long ActingCyclosporinePitavastatin mg QD for days cyclosporine mg/kg on Day 4.6 fold Considered clinically significant [see Dosage and Administration (2.4),Drug Interactions (7)] 6.6 fold ErythromycinPitavastatin mg single dose on Day + erythromycin 500 mg times daily for days 2.8 fold 3.6 fold RifampinPitavastatin mg QD rifampin 600 mg QD for days 29% 2.0 fold AtazanavirPitavastatin mg QD atazanavir 300 mg daily for days 31% 60%Darunavir/RitonavirPitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 26% 4%Lopinavir/RitonavirPitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 20%4 %GemfibrozilPitavastatin mg QD gemfibrozil 600 mg BID for days 45% 31%FenofibratePitavastatin mg QD fenofibrate 160 mg QD for days 18% 11%EzetimibePitavastatin mg QD ezetimibe 10 mg for days 2%0.2%EnalaprilPitavastatin mg QD enalapril 20 mg daily for days 6% 7%DigoxinPitavastatin mg QD digoxin 0.25 mg for days 4% 9%Diltiazem LAPitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-1510%15%Grapefruit JuicePitavastatin mg single dose on Day + grapefruit juice for days 15% 12%ItraconazolePitavastatin mg single dose on Day + itraconazole 200 mg daily for days 23% 22%Table presents the effect of pitavastatin coadministration on systemic exposure of other drugs:Table 4. Effect of Pitavastatin Coadministration on Systemic Exposure to Other DrugsCoadministered drugDosage regimenChange inAUCData presented as change represent difference relative to the investigated drug alone (i.e., 0% no change). Change in Cmax BID twice daily; QD once daily; LA Long ActingAtazanavirPitavastatin mg QD atazanavir 300 mg daily for days 6% 13%DarunavirPitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 3% 6%LopinavirPitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 9% 7%RitonavirPitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 11% 11%RitonavirPitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 8% 2%EnalaprilPitavastatin mg QD enalapril 20 mgdaily for daysEnalapril 12% 12%Enalaprilat 1% 1%WarfarinIndividualized maintenance dose of warfarin (2 7 mg) for days pitavastatin mg QD for daysR-warfarin 7% 3%S-warfarin 6% 3%EzetimibePitavastatin mg QD ezetimibe 10 mg for days 9% 2%DigoxinPitavastatin mg QD digoxin 0.25 mg for days 3% 4%Diltiazem LAPitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 2% 7%RifampinPitavastatin mg QD rifampin 600 mg QD for days 15% 18%.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Primary Hyperlipidemia in Adults. Study with Atorvastatin (Study 301)LIVALO 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 LIVALO 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, LIVALO was non-inferior to atorvastatin for the two pairwise comparisons: LIVALO mg vs. atorvastatin 10 mg and LIVALO 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 LIVALO and Atorvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 301 (Mean Change from Baseline at Week 12)TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO2 mg daily315-38-30-28-144-35LIVALO mg daily298-45-35-32-195-41Atorvastatin 10 mg daily102-38-29-28-183-35Atorvastatin 20 mg daily102-44-36-33-222-41. Study with Simvastatin (Study 302)LIVALO 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 LIVALO 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, LIVALO was non-inferior to simvastatin for the two pairwise comparisons: LIVALO mg vs. simvastatin 20 mg and LIVALO 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 LIVALO and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 302 (Mean Change from Baseline at Week 12)TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO2 mg daily307-39-30-28-166-36LIVALO4 mg daily319-44-35-32-176-41Simvastatin20 mg daily107-35-27-25-166-32Simvastatin40 mg daily110-43-34-31-167-39. Study with Pravastatin in Geriatric Patients (Study 306)LIVALO 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 LIVALO or pravastatin for 12 weeks (Table 7). Non-inferiority of LIVALO 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. LIVALO significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: LIVALO mg vs. pravastatin 10 mg, LIVALO mg vs. pravastatin 20 mg and LIVALO 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 LIVALO and Pravastatin in Geriatric Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 306 (Mean Change from Baseline at Week 12)TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO1 mg daily207-31-25-22-131-29LIVALO2 mg daily224-39-31-27-152-36LIVALO mg daily210-44-37-31-224-41Pravastatin 10 mg daily103-22-17-15-50-20Pravastatin 20 mg daily96-29-22-21-11-1-27Pravastatin 40 mg daily102-34-28-24-151-32. Study with Simvastatin in Patients with >=2 Risk Factors for Coronary Heart Disease (Study 304)LIVALO 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 LIVALO or simvastatin (Table 8). Non-inferiority of LIVALO 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. LIVALO 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 LIVALO 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)TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO4 mg daily233-44-34-31-207-40Simvastatin 40 mg daily118-44-34-31-155-39. Study with Atorvastatin in Patients with Type Diabetes Mellitus (Study 305)LIVALO 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 LIVALO or atorvastatin for 12 weeks. Non-inferiority of LIVALO 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 LIVALO 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 LIVALO and Atorvastatin in Adult Patients with Type Diabetes Mellitus and Mixed Dyslipidemia in Study 305 (Mean Change from Baseline at Week 12)TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO4 mg daily274-41-32-28-207-36Atorvastatin20 mg daily136-43-34-32-278-40The treatment differences in efficacy in LDL-C change from baseline between LIVALO and active controls (i.e., atorvastatin, simvastatin, or pravastatin) in the active-controlled studies described above are summarized in Figure 1.Figure 1. Treatment Difference in Adjusted Mean Percent Change in LDL-C between LIVALO and the Comparator (Atorvastatin, Simvastatin, or Pravastatin) NL=non-inferiority limit. Figure 1. HeFH in Pediatric PatientsIn double-blind, placebo-controlled, 12-week trial, 82 pediatric patients (36 boys and 46 girls), to 16 years of age with genetically confirmed HeFH, fasting low-density lipoprotein cholesterol (LDL-C) >=190 mg/dL or LDL-C >=160 mg/dL with an additional cardiovascular risk factor (male gender, family history of premature CV disease, presence of low HDL (<45 mg/dL) or high TG (>150 mg/dL), presence of high lipoprotein (a) (>75 nmol/L), presence of type diabetes mellitus or presence of hypertension) were randomized to LIVALO mg, mg, and mg. Mean LDL-C at baseline was 235 mg/dL (range 160.5 mg/dL to 441mg/dL). Approximately 39% of patients were Tanner Stage at baseline. LIVALO significantly reduced plasma LDL-C, non-HDL-C, TC, and Apo-B compared to placebo. The reductions in LDL-C, Apo-B, TC, and non-HDL-C were dose dependent. There was no statistically significant improvement in HDL-C or TG at any LIVALO dose. See the lipid results in Table 10.Table 10. Lipid Response in Pediatric Patients with HeFH (Mean Change from Baseline at Week 12)TreatmentNLDL-CApo-BTCTGDifference from placebo not statistically significant Median Percent Change from Baseline at Week 12 HDL-C non-HDL-CPlacebo19-1-3-1-3-1-1LIVALO1 mg daily20-21-20-16-147-21LIVALO2 mg daily24-30-25-25-15-3-29LIVALO4 mg daily19-38-28-305-2-36.

CLINICAL TRIALS EXPERIENCE SECTION.

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 HyperlipidemiaIn 10 controlled clinical studies and subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia were administered LIVALO mg to mg daily. The mean continuous exposure of pitavastatin (1 mg to 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% were 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 LIVALO-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 mg).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 Adults with Primary Hyperlipidemia in Studies up to 12 WeeksAdverse ReactionsPlacebo(n= 208)%LIVALO mg(n=309)%LIVALO mg(n=951)%LIVALO mg(n=1540)%Myalgia1.41.92.83.1Constipation1.93.61.52.2Diarrhea1.92.61.51.9Back pain2.93.91.81.4Pain in extremity1.92.30.60.9Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis.Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with LIVALO.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 LIVALO 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 LIVALO was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with LIVALO had peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with LIVALO had at least one ALT value exceeding times but less than times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with LIVALO, defined as confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than 2-fold increase from baseline.. Adverse Reactions in Pediatric Patients Aged Years and Older with HeFHIn 12-week, double-blind, placebo-controlled trial of LIVALO mg, mg, and mg once daily in 82 pediatric patients years to 16 years of age with HeFH and 52-week open-label trial in 85 pediatric patients with HeFH, the safety profile was similar to that observed in the adult population.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Take orally once daily with or without food at the same time each day. (2.1)For patients requiring high-intensity statin or are unable to achieve their LDL-C goal receiving LIVALO mg daily, prescribe alternative LDL-C-lowering treatment. (2.1)Assess LDL-C when clinically appropriate, as early as weeks after initiation of LIVALO, and adjust the dosage if necessary. (2.1)Recommended dosage is mg to mg once daily. Maximum recommended dosage is mg once daily. (2.2)Recommended starting dosage for patients with moderate and severe renal impairment and end-stage renal disease on hemodialysis is mg once daily. Maximum recommended dosage is mg once daily. (2.3)See full prescribing information for LIVALO dosage modifications due to drug interactions. (2.4). Take orally once daily with or without food at the same time each day. (2.1). For patients requiring high-intensity statin or are unable to achieve their LDL-C goal receiving LIVALO mg daily, prescribe alternative LDL-C-lowering treatment. (2.1). Assess LDL-C when clinically appropriate, as early as weeks after initiation of LIVALO, and adjust the dosage if necessary. (2.1). Recommended dosage is mg to mg once daily. Maximum recommended dosage is mg once daily. (2.2). Recommended starting dosage for patients with moderate and severe renal impairment and end-stage renal disease on hemodialysis is mg once daily. Maximum recommended dosage is mg once daily. (2.3). See full prescribing information for LIVALO dosage modifications due to drug interactions. (2.4). 2.1 Important Dosage and Administration Information. Take LIVALO orally once daily with or without food at the same time each day.For patients that require high-intensity statin or are unable to achieve their LDL-C goal receiving LIVALO mg daily, prescribe alternative LDL-C-lowering treatment.Assess LDL-C when clinically appropriate, as early as weeks after initiating LIVALO, and adjust the dosage if necessary.. Take LIVALO orally once daily with or without food at the same time each day.. For patients that require high-intensity statin or are unable to achieve their LDL-C goal receiving LIVALO mg daily, prescribe alternative LDL-C-lowering treatment.. Assess LDL-C when clinically appropriate, as early as weeks after initiating LIVALO, and adjust the dosage if necessary.. 2.2 Recommended Dosage for Adults and Pediatric Patients Aged Years and Older. The recommended dosage range of LIVALO is mg to mg daily. The maximum recommended dosage is LIVALO mg once daily .. The recommended dosage range of LIVALO is mg to mg daily. The maximum recommended dosage is LIVALO 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 m2 and 15 29 mL/minute/1.73 m2, respectively) and patients with end-stage renal disease receiving hemodialysis is LIVALO mg once daily. The maximum recommended dose for these patients is LIVALO mg once daily [see Use in Specific Populations (8.5)]. There are no dosage adjustment recommendations for patients with mild renal impairment.. The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 59 mL/minute/1.73 m2 and 15 29 mL/minute/1.73 m2, respectively) and patients with end-stage renal disease receiving hemodialysis is LIVALO mg once daily. The maximum recommended dose for these patients is LIVALO mg once daily [see Use in Specific Populations (8.5)]. There are no dosage adjustment recommendations for patients with mild renal impairment.. 2.4 Dosage Modifications Due to Drug Interactions. In patients taking erythromycin, do not exceed LIVALO mg once daily [see Drug Interactions (7)].In patients taking rifampin, do not exceed LIVALO mg once daily [see Drug Interactions (7)].. In patients taking erythromycin, do not exceed LIVALO mg once daily [see Drug Interactions (7)].. In patients taking rifampin, do not exceed LIVALO mg once daily [see Drug Interactions (7)].

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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionPitavastatin peak plasma concentrations are achieved about hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single LIVALO 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 FoodAdministration of LIVALO 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. Elimination. MetabolismThe principal route of pitavastatin metabolism is glucuronidation via liver uridine 5-diphosphate glucuronosyltransferase (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 and UGT2B7). 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. 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 (8.4)]. Pediatric PatientsA 12-week study in pediatric patients to 16 years of age treated with pitavastatin mg, mg and mg administered once daily, showed dose-dependent increase in pitavastatin plasma concentrations at trough (for mg and mg doses) and hour post dose. dose-dependent increase in pitavastatin lactone plasma concentrations was observed at trough and hour post dose.. Male and Female PatientsIn pharmacokinetic study, which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. Racial or Ethnic GroupsIn pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of White healthy volunteers. In pharmacokinetic comparison between White volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.. Patients with Renal ImpairmentIn patients with moderate renal impairment (estimated glomerular filtration rate of 30 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 (8.5)]. In another pharmacokinetic study, patients with severe renal impairment (estimated glomerular filtration rate 15 29 mL/min/1.73 m2) not receiving hemodialysis were administered single dose of LIVALO 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 (8.5)].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 healthy volunteers were 15, 10, and hours, respectively [see Contraindications (4), Warnings and Precautions (5.3)]. Drug Interaction Studies. WarfarinThe steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of LIVALO mg daily.Table presents the effect of coadministered drugs on pitavastatin systemic exposure:Table 3. Effect of Coadministered Drugs on Pitavastatin Systemic ExposureCoadministered drugDosage regimenChange in AUCData 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). Change in Cmax BID twice daily; QD once daily; LA Long ActingCyclosporinePitavastatin mg QD for days cyclosporine mg/kg on Day 4.6 fold Considered clinically significant [see Dosage and Administration (2.4),Drug Interactions (7)] 6.6 fold ErythromycinPitavastatin mg single dose on Day + erythromycin 500 mg times daily for days 2.8 fold 3.6 fold RifampinPitavastatin mg QD rifampin 600 mg QD for days 29% 2.0 fold AtazanavirPitavastatin mg QD atazanavir 300 mg daily for days 31% 60%Darunavir/RitonavirPitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 26% 4%Lopinavir/RitonavirPitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 20%4 %GemfibrozilPitavastatin mg QD gemfibrozil 600 mg BID for days 45% 31%FenofibratePitavastatin mg QD fenofibrate 160 mg QD for days 18% 11%EzetimibePitavastatin mg QD ezetimibe 10 mg for days 2%0.2%EnalaprilPitavastatin mg QD enalapril 20 mg daily for days 6% 7%DigoxinPitavastatin mg QD digoxin 0.25 mg for days 4% 9%Diltiazem LAPitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-1510%15%Grapefruit JuicePitavastatin mg single dose on Day + grapefruit juice for days 15% 12%ItraconazolePitavastatin mg single dose on Day + itraconazole 200 mg daily for days 23% 22%Table presents the effect of pitavastatin coadministration on systemic exposure of other drugs:Table 4. Effect of Pitavastatin Coadministration on Systemic Exposure to Other DrugsCoadministered drugDosage regimenChange inAUCData presented as change represent difference relative to the investigated drug alone (i.e., 0% no change). Change in Cmax BID twice daily; QD once daily; LA Long ActingAtazanavirPitavastatin mg QD atazanavir 300 mg daily for days 6% 13%DarunavirPitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 3% 6%LopinavirPitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 9% 7%RitonavirPitavastatin mg QD on Days 1-5 and 20-24 lopinavir/ritonavir 400 mg/100 mg BID on Days - 24 11% 11%RitonavirPitavastatin 4mg QD on Days 1-5 and 12-16 darunavir/ritonavir 800mg/100 mg QD on Days 6-16 8% 2%EnalaprilPitavastatin mg QD enalapril 20 mgdaily for daysEnalapril 12% 12%Enalaprilat 1% 1%WarfarinIndividualized maintenance dose of warfarin (2 7 mg) for days pitavastatin mg QD for daysR-warfarin 7% 3%S-warfarin 6% 3%EzetimibePitavastatin mg QD ezetimibe 10 mg for days 9% 2%DigoxinPitavastatin mg QD digoxin 0.25 mg for days 3% 4%Diltiazem LAPitavastatin mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 2% 7%RifampinPitavastatin mg QD rifampin 600 mg QD for days 15% 18%.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of LIVALO. 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: angioedema, 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. There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or different statin was administered. 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). Psychiatric disorders: insomnia, depression Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: interstitial lung disease Skin and subcutaneous tissue disorders: lichen planus. 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: angioedema, 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. There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or different statin was administered. 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).. Psychiatric disorders: insomnia, depression. Reproductive system and breast disorders: erectile dysfunction. Respiratory, thoracic and mediastinal disorders: interstitial lung disease. Skin and subcutaneous tissue disorders: lichen planus.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryDiscontinue LIVALO when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient.LIVALO decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LIVALO 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 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 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 drug associated risk of miscarriage (see Data).In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed in pregnant rats and rabbits orally administered pitavastatin during the period of organogenesis at doses which were 22 and times, respectively, the human exposure at the maximum recommended human dosage (MRHD) of mg, based on AUC [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.. Data. Human DataA Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find 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 malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of statin, and lack of information on non-live births.. Animal DataEmbryo-fetal developmental studies were conducted in pregnant rats administered 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis (gestation days 7-17). 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 administered 0.1, 0.3, mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis (gestation days 6-18). 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 (gestation day 17 to lactation day 21), 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). Reproductive 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 (at the end of organogenesis).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause fetal harm. (8.1)Lactation: Breastfeeding not recommended during treatment with LIVALO. (8.2). Pregnancy: May cause fetal harm. (8.1). Lactation: Breastfeeding not recommended during treatment with LIVALO. (8.2). 8.1 Pregnancy. Risk SummaryDiscontinue LIVALO when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient.LIVALO decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LIVALO 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 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 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 drug associated risk of miscarriage (see Data).In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed in pregnant rats and rabbits orally administered pitavastatin during the period of organogenesis at doses which were 22 and times, respectively, the human exposure at the maximum recommended human dosage (MRHD) of mg, based on AUC [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.. Data. Human DataA Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find 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 malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of statin, and lack of information on non-live births.. Animal DataEmbryo-fetal developmental studies were conducted in pregnant rats administered 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis (gestation days 7-17). 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 administered 0.1, 0.3, mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis (gestation days 6-18). 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 (gestation day 17 to lactation day 21), 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). Reproductive 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 (at the end of organogenesis).. 8.2 Lactation. Risk SummaryThere is no available information about the prescence of pitavastatin in human or animal milk, 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. Statins, including LIVALO, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.Because of the potential for serious adverse reactions in breastfed infant, based upon the mechanism of action, advise patients that breastfeeding is not recommended during treatment with LIVALO [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)]. 8.4 Pediatric Use. The safety and effectiveness of LIVALO as an adjunctive therapy to diet to reduce elevated LDL-C in pediatric patients aged years and older with HeFH have been established. Use of LIVALO for this indication is supported by 12-week, double-blind, placebo-controlled trial in 82 pediatric patients to 16 years of age with HeFH [see Clinical Studies (14.2)] and 52-week open-label trial in 85 pediatric patients with HeFH.The safety and effectiveness of LIVALO have not been established in pediatric patients younger than years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH). 8.5 Geriatric Use. In controlled clinical studies, 1,209 (43%) patients were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Advanced age (>=65 years) is risk factor for LIVALO-associated myopathy and rhabdomyolysis. Dose selection for geriatric patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving LIVALO for the increased risk of myopathy [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment. Renal impairment is risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Due to the risk of myopathy, dosage modification of LIVALO is recommended for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 59 mL/min/1.73 m2 and 15 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. LIVALO is contraindicated in patients with active liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

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 LIVALO dosage. Discontinue LIVALO if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue LIVALO 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 LIVALO 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 LIVALO if IMNM is suspected. (5.2)Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LIVALO. (5.3). Myopathy and Rhabdomyolysis: Risk factors include age 65 or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher LIVALO dosage. Discontinue LIVALO if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue LIVALO 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 LIVALO 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 LIVALO if IMNM is suspected. (5.2). Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LIVALO. (5.3). 5.1Myopathy and Rhabdomyolysis. LIVALO 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 result of rhabdomyolysis in patients treated with statins, including LIVALO.. Risk Factors for MyopathyRisk 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 LIVALO dosage [see Dosage and Administration (2.2), Drug Interactions (7), and Use in Specific Populations (8.5, 8.6)]. Dosages of LIVALO greater than mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of LIVALO is mg once daily. Steps to Prevent or Reduce the Risk of Myopathy and RhabdomyolysisLIVALO is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil [see Contraindications (4) and Drug Interactions (7)]. There are LIVALO dosage restrictions for patients taking erythromycin or rifampin [see Dosage and Administration (2.4)]. The following drugs when used concomitantly with LIVALO may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1grams/day), fibrates, and colchicine [see Drug Interactions (7)]. Discontinue LIVALO if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if LIVALO is discontinued. Temporarily discontinue LIVALO 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 LIVALO dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2Immune-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 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 improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue LIVALO if IMNM is suspected.. 5.3Hepatic Dysfunction. Increases in serum transaminases have been reported with LIVALO [see Adverse Reactions (6)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and 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 LIVALO. 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 LIVALO and when clinically indicated thereafter. LIVALO is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LIVALO. 5.4Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including LIVALO. Optimize lifestyle measures, including regular exercise, maintaining healthy body weight, and making healthy food choices.