Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Pitavastatin competitively inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins. Pharmacodynamics In a 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 daily dose). Pharmacokinetics Absorption Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single pitavastatin doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of pitavastatin with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 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. Distribution Pitavastatin 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. Metabolism Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7). Excretion A mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours. Race 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. Gender In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of pitavastatin in women in clinical studies. Geriatric In a pharmacokinetic study which compared healthy young and elderly (≥65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of pitavastatin in elderly subjects in clinical studies. Renal Impairment In patients with moderate renal impairment (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. In another pharmacokinetic study, patients with severe renal impairment (glomerular filtration rate 15 to 29 mL/min/1.73 m²) not receiving hemodialysis were administered a single dose of pitavastatin 4 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%. The effect of mild renal impairment on pitavastatin exposure has not been studied. Hepatic Impairment The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin Cmax between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively. Drug-Drug Interactions The principal route of pitavastatin metabolism is glucuronidation via liver UGTs with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. Warfarin The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of pitavastatin 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when NIKITA is added to their therapy. Table 2: Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure Co-administered drug Dose regimen Change in AUC* Change in C * vmax Cyclosporine Pitavastatin 2 mg QD for 6 days + cyclosporine 2 mg/kg on Day 6 ↑ 4.6 fold† ↑ 6.6 fold † Erythromycin Pitavastatin 4 mg single dose on Day 4 + erythromycin 500 mg 4 times daily for 6 days ↑ 2.8 fold † ↑ 3.6 fold † Rifampin Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 days ↑ 29% ↑2.0 fold Atazanavir Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 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 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 - 24 ↓ 20% ↓4 % Gemfibrozil Pitavastatin 4 mg QD + gemfibrozil 600 mg BID for 7 days ↑ 45% ↑ 31% Fenofibrate Pitavastatin 4 mg QD + fenofibrate 160 mg QD for 7 days ↑18% ↑ 11% Ezetimibe Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days ↓ 2% ↓0.2% Enalapril Pitavastatin 4 mg QD + enalapril 20 mg daily for 5 days ↑6% ↓ 7% Digoxin Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days ↑ 4% ↓ 9% Diltiazem LA Pitavastatin 4 mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 ↑10% ↑15% Grapefruit Juice Pitavastatin 2 mg single dose on Day 3 + grapefruit juice for 4 days ↑ 15% ↓ 12% Itraconazole Pitavastatin 4 mg single dose on Day 4 + itraconazole 200 mg daily for 5 days ↓23% ↓22% *Data presented as x-fold change represent the ratio between co-administration 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 and DRUG INTERACTIONS] BID = twice daily; QD = once daily; LA = Long Acting Table 3: Effect of Pitavastatin Co-Administration on Systemic Exposure to Other Drugs Co-administered drug Dose regimen Change in AUC* Change in Cmax* Atazanavir Pitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days ↑6% ↑13% Darunavir Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 616 ↑ 3% ↑6% Lopinavir Pitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 - 24 ↓ 9% ↓ 7% Ritonavir Pitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 - 24 ↓11% ↓11% Ritonavir Pitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 616 ↑ 8% ↑2% Enalapril Pitavastatin 4 mg QD + enalapril 20 mg daily for 5 days Enalapril ↑12% ↑ 12% Enalaprilat ↓ 1% ↓ 1% Warfarin Individualized maintenance dose of warfarin (2 -7 mg) for 8 days + pitavastatin 4 mg QD for 9 days R-warfarin ↑7% ↑ 3% S-warfarin ↑ 6% ↑ 3% Ezetimibe Pitavastatin 2 mg QD + ezetimibe 10 mg for 7 days ↑ 9% ↑ 2% Digoxin Pitavastatin 4 mg QD + digoxin 0.25 mg for 7 days ↓ 3% ↓4% Diltiazem LA Pitavastatin 4 mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15 ↓2% ↓7% Rifampin Pitavastatin 4 mg QD + rifampin 600 mg QD for 5 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 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. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a 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 a dose level of 1 mg/kg/day (9 times clinical exposure at the maximum human dose of 4 mg/day based on AUC comparisons). Clinical Studies Primary Hyperlipidemia Or Mixed Dyslipidemia Dose-ranging study A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was performed to evaluate the efficacy of pitavastatin compared with placebo in 251 patients with primary hyperlipidemia (Table 4). Pitavastatin given as a single daily dose for 12 weeks significantly reduced plasma LDL-C, TC, TG, and Apo-B compared to placebo and was associated with variable increases in HDL-C across the dose range. Table 4: Dose-Response in Patients with Primary Hypercholesterolemia (Adjusted Mean % Change from Baseline at Week 12) Treatment N LDL-C Apo-B TC TG HDL-C Placebo 53 -3 -2 -2 1 0 Pitavastatin 1mg 52 -32 -25 -23 -15 8 Pitavastatin 2mg 49 -36 -30 -26 -19 7 Pitavastatin 4mg 51# -43 -35 -31 -18 5 #The number of subjects for Apo-B was 49 Active-Controlled Study With Atorvastatin (NK-104-301) Pitavastatin was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 817 patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either pitavastatin or atorvastatin (Table 5). Non-inferiority of pitavastatin to a 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 2 mg vs. atorvastatin 10 mg and pitavastatin 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively. Table 5: Response by Dose of Pitavastatin and Atorvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12) Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin 2 mg daily 315 -38 -30 -28 -14 4 -35 Pitavastatin 4 mg daily 298 -45 -35 -32 -19 5 -41 Atorvastatin 10 mg daily 102 -38 -29 -28 -18 3 -35 Atorvastatin 20 mg daily 102 -44 -36 -33 -22 2 -41 Atorvastatin 40 mg daily ..........................Not Studied.......................... Atorvastatin 80 mg daily ..........................Not Studied.......................... Active-Controlled Study With Simvastatin (NK-104-302) Pitavastatin was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 843 patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12 week treatment with either pitavastatin or simvastatin (Table 6). Non-inferiority of pitavastatin to a 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 2 mg vs. simvastatin 20 mg and pitavastatin 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively. Table 6: Response by Dose of Pitavastatin and Simvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12) Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin 2 mg daily 307 -39 -30 -28 -16 6 -36 Pitavastatin 4 mg daily 319 -44 -35 -32 -17 6 -41 Simvastatin 20 mg daily 107 -35 -27 -25 -16 6 -32 Simvastatin 40 mg daily 110 -43 -34 -31 -16 7 -39 Simvastatin 80 mg daily ..........................Not Studied--........................ Active-Controlled Study With Pravastatin In Elderly (NK-104-306) Pitavastatin was compared with the HMG-CoA reductase inhibitor pravastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority Phase 3 study of 942 elderly patients (≥65 years) with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6-to 8-week wash-out/dietary lead-in period, and then were randomized to a once daily dose of pitavastatin or pravastatin for 12 weeks (Table 7). Non-inferiority of pitavastatin to a 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 1 mg vs. pravastatin 10 mg, pitavastatin 2 mg vs. pravastatin 20 mg and pitavastatin 4 mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively. Table 7: Response by Dose of Pitavastatin and Pravastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12) Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin 1 mg daily 207 -31 -25 -22 -13 1 -29 Pitavastatin 2 mg daily 224 -39 -31 -27 -15 2 -36 Pitavastatin 4 mg daily 210 -44 -37 -31 -22 4 -41 Pravastatin 10 mg daily 103 -22 -17 -15 -5 0 -20 Pravastatin 20 mg daily 96 -29 -22 -21 -11 -1 -27 Pravastatin 40 mg daily 102 -34 -28 -24 -15 1 -32 Pravastatin 80 mg daily .........................-Not Studied.......................... Active-Controlled Study With Simvastatin In Patients With ≥ 2 Risk Factors For Coronary Heart Disease (NK-104-304) Pitavastatin was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 351 patients with primary hyperlipidemia or mixed dyslipidemia with ≥2 risk factors for coronary heart disease. After a 6-to 8-week wash-out/dietary lead-in period, patients were randomized to a 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 4 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: Response by Dose of Pitavastatin and Simvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia with ≥2 Risk Factors for Coronary Heart Disease (Mean % Change from Baseline at Week 12) Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin 4 mg daily 233 -44 -34 -31 -20 7 -40 Simvastatin 40 mg daily 118 -44 -34 -31 -15 5 -39 Simvastatin 80 mg daily ..........................Not Studied.......................... Active-Controlled Study With Atorvastatin In Patients With Type II Diabetes Mellitus (NK-104-305) Pitavastatin was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority Phase 3 study of 410 subjects with type II diabetes mellitus and combined dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and were randomized to a 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 so that the non-inferiority objective was not achieved. Table 9: Response by Dose of Pitavastatin and Atorvastatin in Patients with Type II Diabetes Mellitus and Combined Dyslipidemia (Mean % Change from Baseline at Week 12) Treatment N LDL-C Apo-B TC TG HDL-C non-HDL-C Pitavastatin 4 mg daily 274 -41 -32 -28 -20 7 -36 Atorvastatin 20 mg daily 136 -43 -34 -32 -27 8 -40 Atorvastatin 40 mg daily .........................-Not Studied.......................... Atorvastatin 80 mg daily .........................-Not Studied.......................... The treatment differences in efficacy in LDL-C change from baseline between pitavastatin and active controls in the Phase 3 studies are summarized in Figure 1. Figure 1: Treatment Difference in Adjusted Mean Percent Change in LDL-C NL=non-inferiority limit.

NIKITA (pitavastatin) Tablet DESCRIPTION NIKITA (pitavastatin) is an inhibitor of HMG-CoA reductase. It is a synthetic lipid-lowering agent for oral administration. The chemical name for pitavastatin is Sodium (3R, 5S, E)-7-(2-cyclopropyl-4-(4-fluorophenyl)­quinolin-3-yl)-3, 5-dihydroxyhept-6-enoate. The structural formula is: The empirical formula for pitavastatin is C25H23FNO4Na and the molecular weight is 443.15. Pitavastatin occurs as white to pale yellow powder. It is slightly soluble in N, N-Dimethylformamide. Pitavastatin is slightly hygroscopic in nature and slightly unstable in light. Each film-coated tablet of NIKITA contains 1.052 mg, 2.103 mg, or 4.206 mg of pitavastatin sodium, which is equivalent to 1 mg, 2 mg, or 4 mg, respectively of pitavastatin, and the following inactive ingredients: hypromellose, lactose monohydrate, low substituted hydroxypropylcellulose, magnesium stearate and sodium bicarbonate and film coating containing the following inactive ingredients: colloidal anhydrous silica, hypromellose, titanium dioxide and triethyl citrate.

INDICATIONS Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate. Primary Hyperlipidemia And Mixed Dyslipidemia NIKITA is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia. Limitations Of Use Doses of NIKITA greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4 mg once daily dosing of NIKITA. The effect of NIKITA on cardiovascular morbidity and mortality has not been determined. NIKITA has not been studied in Fredrickson Type I, III, and V dyslipidemias. DOSAGE AND ADMINISTRATION General Dosing Information The dose range for NIKITA is 1 to 4 mg orally once daily at any time of the day with or without food. The recommended starting dose is 2 mg and the maximum dose is 4 mg. The starting dose and maintenance doses of NIKITA should be individualized according to patient characteristics, such as goal of therapy and response. After initiation or upon titration of NIKITA, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly. Dosage In Patients With Renal Impairment Patients with moderate and severe renal impairment (glomerular filtration rate 30 to 59 mL/min/1.73 m² and 15 to 29 mL/min/1.73 m² not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of NIKITA 1 mg once daily and a maximum dose of NIKITA 2 mg once daily. Use With Erythromycin In patients taking erythromycin, a dose of NIKITA 1 mg once daily should not be exceeded [see DRUG INTERACTIONS]. Use With Rifampin In patients taking rifampin, a dose of NIKITA 2 mg once daily should not be exceeded [see DRUG INTERACTIONS]. HOW SUPPLIED Dosage Forms And Strengths 1 mg: White to off-white, round, film-coated tablets, debossed with “LU” on one side and “C75” on the other side. 2 mg: White to off-white, round, film-coated tablets, debossed with “LU” on one side and “C76” on the other side. 4 mg: White to off-white, round, film-coated tablets, debossed with “LU” on one side and “C77” on the other side. Storage And Handling NIKITA tablets for oral administration are provided as white, film-coated tablets that contain 1 mg, 2 mg, or 4 mg of pitavastatin. Each tablet has “LU” debossed on one side and a code number specific to the tablet strength on the other. Packaging NIKITA (pitavastatin) Tablets are supplied as; 1 mg: White to off-white round film-coated tablets debossed with “LU” on one side and “C75” on the other side. Bottle of 30 tablets (NDC 68180-742-06). Bottle of 60 tablets (NDC 68180-742-07). Bottle of 90 tablets (NDC 68180-742-09). 2 mg: White to off-white round film-coated tablets debossed with “LU” on one side and “C76” on the other side. Bottle of 30 tablets (NDC 68180-743-06). Bottle of 60 tablets (NDC 68180-743-07). Bottle of 90 tablets (NDC 68180-743-09). 4 mg: White to off-white round film-coated tablets debossed with “LU” on one side and “C77” on the other side. Bottle of 30 tablets (NDC 68180-744-06). Bottle of 60 tablets (NDC 68180-744-07). Bottle of 90 tablets (NDC 68180-744-09). Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Manufactured for: Lupin Pharmaceuticals, Inc., Baltimore, Maryland 21202 United States. Manufactured by: Lupin Limited, Nagpur 441 108 INDIA. Revised: Aug 2017

PATIENT INFORMATION The patient should be informed of the following: Dosing Time NIKITA can be taken at any time of the day with or without food. Muscle Pain Patients should be advised to promptly notify their physician of any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever, or if these muscle signs or symptoms persist after discontinuing NIKITA. They should discuss all medication, both prescription and over the counter, with their physician. Embryo-fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment and to inform their healthcare professional of a known or suspected pregnancy [see CONTRAINDICATIONS, Use In Specific Populations]. Lactation Advise women not to breastfeed during treatment with NIKITA [see CONTRAINDICATIONS, Use In Specific Populations]. Liver Enzymes It is recommended that liver enzyme tests be checked before the initiation of NIKITA and if signs or symptoms of liver injury occur. All patients treated with NIKITA should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

SIDE EFFECTS The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see WARNINGS AND PRECAUTIONS]. Liver Enzyme Abnormalities [see WARNING AND PRECAUTIONS]. Of 4,798 patients enrolled in 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 patients were administered pitavastatin 1 mg to 4 mg daily. The mean continuous exposure of pitavastatin (1 mg to 4 mg) was 36.7 weeks (median 51.1 weeks). The mean age of the patients was 60.9 years (range; 18 years to 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. Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in ≥2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks. Table 1: Adverse Reactions* Reported by ≥2% of Patients Treated with Pitavastatin and > Placebo in Short-Term Controlled Studies Adverse Reactions* Placebo N= 208 Pitavastatin 1 mg N=309 Pitavastatin 2 mg N=951 Pitavastatin 4 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 % * Adverse reactions by MedDRA preferred term. Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis. The following laboratory abnormalities have also been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose. In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin-treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg). Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with pitavastatin. In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either pitavastatin 4 mg once daily (n=126) or another statin (n=126). All patients were taking antiretroviral therapy (excluding darunavir) and had HIV-1 RNA less than 200 copies/mL and CD4 count greater than 200 cell/μL for at least 3 months prior to randomization. The safety profile of pitavastatin was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with pitavastatin had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (10x ULN), which resolved spontaneously. Four patients (3%) treated with pitavastatin had at least one ALT value exceeding 3x but less than 5x ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with pitavastatin, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline. Postmarketing Experience The following adverse reactions have been identified during postapproval use of pitavastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions associated with pitavastatin therapy reported since market introduction, regardless of causality assessment, include the following: abdominal discomfort, abdominal pain, dyspepsia, nausea, asthenia, fatigue, malaise, hepatitis, jaundice, fatal and non-fatal hepatic failure, dizziness, hypoesthesia, insomnia, depression, interstitial lung disease, erectile dysfunction, muscle spasms and peripheral neuropathy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see WARNINGS AND PRECAUTIONS]. DRUG INTERACTIONS Cyclosporine Cyclosporine significantly increased pitavastatin exposure. Co-administration of cyclosporine with NIKITA is contraindicated [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. Erythromycin Erythromycin significantly increased pitavastatin exposure. In patients taking erythromycin, a dose of NIKITA 1 mg once daily should not be exceeded [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Rifampin Rifampin significantly increased pitavastatin exposure. In patients taking rifampin, a dose of NIKITA 2 mg once daily should not be exceeded [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of NIKITA with gemfibrozil should be avoided. Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, NIKITA should be administered with caution when used concomitantly with other fibrates [see WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY]. Niacin The risk of skeletal muscle effects may be enhanced when NIKITA is used in combination with niacin; a reduction in NIKITA dosage should be considered in this setting [see WARNINGS AND PRECAUTIONS]. Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing NIKITA with colchicine. Warfarin Pitavastatin had no significant pharmacokinetic interaction with R-and S-warfarin. Pitavastatin had no significant effect on prothrombin time (PT) and international normalized ratio (INR) when administered to patients receiving chronic warfarin treatment [see CLINICAL PHARMACOLOGY]. However, patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to their therapy.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including pitavastatin. These risks can occur at any dose level, but increase in a dose-dependent manner. NIKITA should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (≥65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy may also be increased with concurrent administration of fibrates or lipid-modifying doses of niacin. NIKITA should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin [see DRUG INTERACTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing NIKITA with colchicine [see DRUG INTERACTIONS]. 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; improvement with immunosuppressive agents. NIKITA therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. NIKITA therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing NIKITA. Liver Enzyme Abnormalities Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including pitavastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. In placebo-controlled Phase 2 studies, ALT >3 times the upper limit of normal was not observed in the placebo, pitavastatin 1 mg, or pitavastatin 2 mg groups. One out of 202 patients (0.5%) administered pitavastatin 4 mg had ALT >3 times the upper limit of normal. It is recommended that liver enzyme tests be performed before the initiation of NIKITA and if signs or symptoms of liver injury occur. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with NIKITA, promptly interrupt therapy. If an alternate etiology is not found do not restart NIKITA. As with other HMG-CoA reductase inhibitors, NIKITA should be used with caution in patients who consume substantial quantities of alcohol. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of NIKITA [see CONTRAINDICATIONS]. Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including pitavastatin. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility In a 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 4 mg/day, there was an absence of drug-related tumors. In a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was a 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 4 mg/day maximum human dose. In a 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 a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a 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 4 mg/day based on AUC. Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30-times clinical systemic exposure at 4 mg/day based on AUC) and higher during a 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. Use In Specific Populations Pregnancy Risk Summary NIKITA 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 NIKITA during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, NIKITA may cause fetal harm when administered to pregnant women. NIKITA should be discontinued as soon as pregnancy is recognized [see CONTRAINDICATIONS]. Limited published data on the use of pitavastatin are insufficient to determine a 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 4 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. Data Human Data Limited published data on pitavastatin have not reported a 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 a 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 a greater than or equal to a 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 Data 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 a single dose of 1 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 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC. Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, 1 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 4 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 1 time human systemic exposure at 4 mg/day dose based on AUC). Lactation Risk Summary NIKITA is contraindicated during breastfeeding [see CONTRAINDICATIONS]. 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 a breastfed infant, advise patients that breastfeeding is not recommended during treatment with NIKITA. Females And Males Of Reproductive Potential Contraception Females NIKITA may cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with NIKITA. Pediatric Use Safety and effectiveness of NIKITA in pediatric patients have not been established. Geriatric Use Of the 2,800 patients randomized to pitavastatin 1 mg to 4 mg in controlled clinical studies, 1,209 (43%) were 65 years and older. No significant differences in efficacy or safety were observed between elderly patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. Renal Impairment Patients with moderate and severe renal impairment (glomerular filtration rate 30 to 59 mL/min/1.73 m² and 15 to 29 mL/min/1.73 m² not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of NIKITA 1 mg once daily and a maximum dose of NIKITA 2 mg once daily [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Hepatic Impairment NIKITA is contraindicated in patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.