RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

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DESCRIPTION SECTION

11 DESCRIPTION

LIVALO (pitavastatin) tablets for oral use is an HMG-CoA reductase inhibitor.

The chemical name for pitavastatin is (+)monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}. The structural formula is:

The empirical formula for pitavastatin is C50H46CaF2N2O8 and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is 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 LIVALO 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: hypromellose, lactose monohydrate, low substituted hydroxypropylcellulose, magnesium aluminometasilicate, and magnesium stearate. The film coating contains the following inactive ingredients: colloidal anhydrous silica, hypromellose, titanium dioxide, and triethyl citrate.

CLINICAL PHARMACOLOGY SECTION

12 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, 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 4 mg daily).

12.3 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 LIVALO doses from 1 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 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 LIVALO with a high fat meal (50% fat content) decreases pitavastatin Cmax 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 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.

Specific Populations

Geriatric Patients

In a 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 Patients

A 12-week study in pediatric patients 8 to 16 years of age treated with pitavastatin 1 mg, 2 mg and 4 mg administered once daily, showed a dose- dependent increase in pitavastatin plasma concentrations at trough (for 2 mg and 4 mg doses) and 1 hour post dose. A dose-dependent increase in pitavastatin lactone plasma concentrations was observed at trough and 1 hour post dose.

Male and Female Patients

In a pharmacokinetic study, which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females.

Racial or Ethnic Groups

In pharmacokinetic studies pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of White healthy volunteers. In pharmacokinetic comparison between White volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.

Patients with Renal Impairment

In 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 a single dose of LIVALO 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% [see Use in Specific Populations (8.5)].

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 Cmax and AUCinf 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 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 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 LIVALO 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

Table 4 presents the effect of pitavastatin coadministration on systemic exposure of other drugs:

Table 4. Effect of Pitavastatin Coadministration on Systemic Exposure to Other Drugs

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INDICATIONS & USAGE SECTION

Highlight: LIVALO is a HMG-CoA reductase inhibitor (statin) indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: (1)

• Adults with primary hyperlipidemia.
• Adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH).

1 INDICATIONS AND USAGE

LIVALO is indicated as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in:

• Adults with primary hyperlipidemia.
• Adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH).

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Tablets: 1 mg, 2 mg, and 4 mg (3)

3 DOSAGE FORMS AND STRENGTHS

Tablets:

• 1 mg: Round white tablet, debossed "KC" on one side and "1" on the other side.
• 2 mg: Round white tablet, debossed "KC" on one side and "2" on the other side.
• 4 mg: Round white tablet, debossed "KC" on one side and "4" on the other side.

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CONTRAINDICATIONS SECTION

Highlight: * Cyclosporine (4, 7)

• Active liver failure or decompensated cirrhosis (4, 5.3)
• Hypersensitivity to pitavastatin or any excipients in LIVALO (4)

4 CONTRAINDICATIONS

LIVALO is 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 excipents in LIVALO. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with LIVALO [see Adverse Reactions (6)].

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: May cause fetal harm. (8.1)

• Lactation: Breastfeeding not recommended during treatment with LIVALO. (8.2)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Discontinue 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 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 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 (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 1 time human systemic exposure at 4 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 a single dose of 1 mg/kg/day during gestation (at the end of organogenesis).

8.2 Lactation

Risk Summary

There 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 a 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 8 years and older with HeFH have been established. Use of LIVALO for this indication is supported by a 12-week, double-blind, placebo-controlled trial in 82 pediatric patients 8 to 16 years of age with HeFH [see Clinical Studies (14.2)] and a 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 8 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 a risk factor for LIVALO-associated myopathy and rhabdomyolysis. Dose selection for a geriatric patient should be cautious, reognizing 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 a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Due to the risk of myopathy, a 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)].

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ADVERSE REACTIONS SECTION

Highlight: 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 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)].

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 LIVALO 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 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 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

Other 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 Dyslipidemia

In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either LIVALO 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 LIVALO was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with LIVALO had a 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 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 LIVALO, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline.

Adverse Reactions in Pediatric Patients Aged 8 Years and Older with HeFH

In a 12-week, double-blind, placebo-controlled trial of LIVALO 1 mg, 2 mg, and 4 mg once daily in 82 pediatric patients 8 years to 16 years of age with HeFH and a 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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 a 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 3 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

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OVERDOSAGE SECTION

10 OVERDOSAGE

No specific treatment for LIVALO 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 LIVALO.

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SPL UNCLASSIFIED SECTION

Manufactured for:
Kowa Company, Limited Tokyo 103-8433 Japan
Manufactured by:
Patheon, Inc. Cincinnati, OH 45237 USA or by Kowa Company, LTD Nagoya, 462-0024 Japan
Marketed and Distributed by:
Kowa Pharmaceuticals America, Inc. Montgomery, AL 36117 USA

LIV-RA-0148 01/2024
LIVALO is a trademark of the Kowa group of companies.
© Kowa Pharmaceuticals America, Inc. (2009)

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