Pitavastatin

Contraindications, Pregnancy and Lactation ( 4 ) Removed 03/2023 Warnings and Precautions, Immune-Mediated Necrotizing Myopathy ( 5.2 ) 03/2023

1 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).

2 DOSAGE AND ADMINISTRATION Take orally once daily with or without food at the same time each day ( 2.1 ). For patients requiring a high-intensity statin or are unable to achieve their LDL-C goal receiving 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.

3 DOSAGE FORMS AND STRENGTHS Tablets: 1 mg: White to off-white circular biconvex film-coated tablets. Debossed with the logo “OP” on one side and “57” on the other side of the tablet. 2 mg: White to off-white circular biconvex film-coated tablets. Debossed with the logo “OP” on one side and “58” on the other side of the tablet. 4 mg: White to off-white circular biconvex film-coated tablets. Debossed with the logo “OP” on one side and “59” on the other side of the tablet. Tablets: 1 mg, 2 mg, and 4 mg ( 3 )

4 CONTRAINDICATIONS Pitavastatin tablets are contraindicated in the following conditions: Concomitant use of cyclosporine [see Drug Interactions ( 7 )] . Acute liver failure or decompensated cirrhosis [see Warning 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 )

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 )]. The most frequent adverse reactions (rate ≥2%) were myalgia, constipation, back pain, diarrhea, and pain in extremity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Orient Pharma Co., Ltd. at 1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of one drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults with Primary Hyperlipidemia In 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia were administered pitavastatin tablets 1 mg to 4 mg daily. The mean continuous exposure of pitavastatin (1 mg to 4 mg) was 36.7 weeks (median 51.1 weeks). The mean age of the patients was 60.9 years (range; 18 years – 89 years) and 52% 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 pitavastatin tablets -treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg). Adverse reactions reported in ≥ 2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks. Table 1. Adverse Reactions ( ≥ 2% and ≥ placebo) in Adults with Primary Hyperlipidemia in Studies up to 12 Weeks Adverse Reactions Placebo (n= 208) % Pitavastatin Tablets 1 mg (n=309) % Pitavastatin Tablets 2 mg (n=951) % Pitavastatin Tablets 4 mg (n=1540) % Myalgia 1.4 1.9 2.8 3.1 Constipation 1.9 3.6 1.5 2.2 Diarrhea 1.9 2.6 1.5 1.9 Back Pain 2.9 3.9 1.8 1.4 Pain in extremity 1.9 2.3 0.6 0.9 Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with Pitavastatin tablets. The following laboratory abnormalities have been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose. Adverse Reactions in Adult HIV-Infected Patients with Dyslipidemia In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either pitavastatin tablets 4mg 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 tablets was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with pitavastatin tablets had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with pitavastatin tablets had at least one ALT value exceeding 3 times but less than 5 times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with pitavastatin tablets, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from b …

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

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended during treatment with pitavastatin tablets. ( 8.2 ) See 17 for PATIENT COUNSELING INFORMATION. 8.1 Pregnancy Risk Summary Discontinue pitavastatin tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Pitavastatin tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pitavastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with statin use in pregnant women are insufficient to determine if there is a drug associated risk of miscarriage [see Data]. In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed in pregnant rats and rabbits orally administered pitavastatin during the period of organogenesis at doses which were 22 and 4 times, respectively, the human exposure at the maximum recommended human dosage (MRHD) of 4 mg, based on AUC [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Embryo-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 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC. Embryo-fetal developmental studies were conducted in pregnant rabbits administered 0.1, 0.3, 1 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 sy …

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.

11 DESCRIPTION Pitavastatin tablets for oral use is an HMG-CoA reductase inhibitor. The chemical name for pitavastatin is (+)monocalcium bis {(3R, 5S, 6 E )-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}. The structural formula is: The empirical formula for pitavastatin is C 50 H 46 CaF 2 N 2 O 8 and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is freely soluble in pyridine, chloroform, dilute hydrochloric acid, and tetrahydrofuran, soluble in ethylene glycol, sparingly soluble in octanol, slightly soluble in methanol, very slightly soluble in water or ethanol, and practically insoluble in acetonitrile or diethyl ether. Pitavastatin is hygroscopic and slightly unstable in light. Each film-coated tablet of pitavastatin tablets contains 1 mg, 2 mg, or 4 mg of pitavastatin, which is equivalent to 1.045 mg, 2.09 mg, or 4.18 mg, respectively, of pitavastatin calcium and the following inactive ingredients: crospovidone, lactose monohydrate, microcrystalline cellulose, magnesium oxide, magnesium stearate, povidone, sodium starch glycolate, and film coating containing the following inactive ingredients: hypromellose, lactose monohydrate, titanium dioxide, and triacetin. structural formula

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

16 HOW SUPPLIED/STORAGE AND HANDLING Pitavastatin tablets, 1 mg are supplied as white to off-white colored, round shaped, beveled edges, film-coated tablets, debossed with “AN” on one side and “029” on the other side. They are available as follows: Bottles of 30: NDC 65162-029-03 Bottles of 90: NDC 65162-029-09 Bottles of 500: NDC 65162-029-50 Pitavastatin tablets, 2 mg are supplied as white to off-white colored, round shaped, beveled edges, film-coated tablets, debossed with “AN” on one side and “030” on the other side. They are available as follows: Bottles of 30: NDC 65162-030-03 Bottles of 90: NDC 65162-030-09 Bottles of 500: NDC 65162-030-50 Pitavastatin tablets, 4 mg are supplied as white to off-white colored, round shaped, film-coated tablets, debossed with “AN” on one side and “031” on the other side. They are available as follows: Bottles of 30: NDC 65162-031-03 Bottles of 90: NDC 65162-031-09 Bottles of 500: NDC 65162-031-50 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light.