pitavastatin sodium 4 MG Oral Tablet [Nikita]

INDICATIONS AND USAGE Pitavastatin tablets are indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: Adult with primary hyperlipidemia. Adults with heterozygous familial hypercholesterolemia (HeFH). Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information. Pitavastatin is a HMG-CoA reductase inhibitor (statin) indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: ( 1 ) Adult patients with primary hyperlipidemia. Adults with heterozygous familial hypercholesterolemia (HeFH).

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

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 pitavastatin tablets dosage. Discontinue pitavastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue pitavastatin tablets 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 pitavastatin tablets 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 pitavastatin tablets 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 pitavastatin tablets. ( 5.3 ) 5.1 Myopathy and Rhabdomyolysis Pitavastatin tablets may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including pitavastatin tablets. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use of certain drugs (including other lipid-lowering therapies), and higher pitavastatin tablets dosage [see Dosage and Administration (2.2) , Drug Interactions (7) , and Use in Specific Populations (8.5 , 8.6) ] . Dosages of pitavastatin tablets greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of pitavastatin tablets is 4 mg once daily. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Pitavastatin tablets are contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil [see Contraindications (4) and Drug Interactions (7) ] . There are pitavastatin tablets dosage restrictions for patients taking erythromycin or rifampin [see Dosage and Administration (2.4) ] . The following drugs when used concomitantly with pitavastatin tablets may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (> 1 grams/day), fibrates, and colchicine [see Drug Interactions (7) ] . Discontinue pitavastatin tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if pitavastatin tablets are discontinued. Temporarily discontinue pitavastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the pitavastatin tablets dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue pitavastatin tablets if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with pitavastatin tablets [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 a brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin tablets. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before the initiation of pitavastatin tablets and when clinically indicated thereafter. Pitavastatin tablets are 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 pitavastatin tablets. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pitavastatin tablets. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

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

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the biosynthetic pathway for cholesterol. 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. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low density lipoproteins. 12.2 Pharmacodynamics Cardiac Electrophysiology In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, pitavastatin tablets were 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 4 mg daily). 12.3 Pharmacokinetics Absorption Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both C max and AUC 0-inf increased in an approximately dose-proportional manner for single pitavastatin tablets doses from 1 mg to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. The C max 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. Effect of Food Administration of pitavastatin tablets with a high fat meal (50% fat content) decreases pitavastatin C max by 43% but does not significantly reduce pitavastatin AUC. 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. Elimination Metabolism The 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 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 UGTs (UGT1A3 and UGT2B7). Excretion A mean of 15% of radioactivity of orally administered, single 32 mg 14 C-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. Specific Populations Geriatric Patients In a pharmacokinetic study which compared healthy young and geriatric (≥65 years) volunteers, pitavastatin C max and AUC were 10 and 30% higher, respectively, in the geriatric patients [see Use in Specific Populations ( 8.5 )] Pediatric Patients Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information. Male and Female Patients In a pharmacokinetic study, which compared healthy male and female volunteers, pitavastatin C max and AUC were 60 and 54% higher, respectively in females. Racial or Ethnic Groups In pharmacokinetic studies pitavastatin C max 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 C max and AUC. Patients with Renal Impairment In patients with moderate renal impairment (estimated glomerular filtration rate of 30 – 59 mL/min/1.73 m 2 ) and end stage renal disease receiving hemodialysis, pitavastatin AUC 0-inf is 102% and 86% higher than those of healthy volunteers, respectively, while pitavastatin C max is 60% and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33% and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively [see Use in Specific Populations ( 8.6 )]. In another pharmacokinetic study, patients with severe renal impairment (estimated glomerular filtration rate 15 – 29 mL/min/1.73 m 2 ) not receiving hemodialysis were administered a single dose of pitavastatin tablets 4 mg. The AUC 0-inf and the C max were 36% and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6% [see Use in Specific Populations ( 8.6 )]. The effect of mild renal impairment on pitavastatin exposure has not been studied. Patients with Hepatic Impairment The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. Pitavastatin C max and AUC inf in patients with moderate hepatic impairment (Child-Pugh B disease) was 2.7-fold and 3.8-fold higher, respectively as compared to healthy volunteers. In patients with mild hepatic impairment (Child-Pugh A disease), pitavastatin C max and AUC inf 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 8 hours, respectively [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )]. Drug Interaction Studies Warfarin The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of pitavastatin tablets 4 mg daily. Table 3 presents the effect of coadministered drugs on pitavastatin systemic exposure: Table 3. Effect of Coadministered Drugs on Pitavastatin Systemic Exposure Coadministered drug Dosage regimen Change in AUC* Change in C max * 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 4 mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800 mg/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 coadministration and pitavastatin alone (i.e., 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (i.e., 0% = no change). † Considered clinically significant [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7 )] BID = twice daily; QD = onc