LIVALO® (pitavastatin) Tablet
`1 mg, 2 mg, and 4 mg
`
`Kowa Pharmaceuticals America, Inc.
`
`Montgomery, AL 36117
`
`Package Insert – Product Labeling
`Version of October 2013
`Version 8.0
`
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`Sawai USA, Inc., et al. v. Nissan
`
` Chemical Industries, Ltd.
`
`NCI Exhibit 2002
`Case IPR 2015-01647
`
`

`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`LIVALO® safely and effectively. See full prescribing information for
`LIVALO.
`LIVALO (pitavastatin) Tablet, Film Coated for Oral use
`Initial U.S. Approval: 2009
`
`None
`
`RECENT MAJOR CHANGES
`
`INDICATIONS AND USAGE
`LIVALO is a HMG-CoA reductase inhibitor indicated for:
`• Patients with primary hyperlipidemia or mixed dyslipidemia 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 high-density lipoprotein cholesterol
`(HDL-C) (1.1)
`
`Limitations of Use (1.2):
`• Doses of LIVALO 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 LIVALO.
`• The effect of LIVALO on cardiovascular morbidity and mortality has not
`been determined.
`• LIVALO has not been studied in Fredrickson Type I, III, and V
`dyslipidemias.
`
`DOSAGE AND ADMINISTRATION
`• LIVALO can be taken with or without food, at any time of day (2.1) Dose
`Range: 1 mg to 4 mg once daily (2.1)
`• Primary hyperlipidemia and mixed dyslipidemia: Starting dose 2 mg.
`When lowering of LDL-C is insufficient, the dosage may be increased to a
`maximum of 4 mg per day. (2.1)
`• Moderate and severe renal impairment (glomerular filtration rate 30 –
`59 and 15 - 29 mL/min/1.73 m2, respectively) as well as end-stage renal
`disease on hemodialysis: Starting dose of 1 mg once daily and maximum
`dose of 2 mg once daily (2.2)
`
`DOSAGE FORMS AND STRENGTHS
`• Tablets: 1 mg, 2 mg, and 4 mg (3)
`
`CONTRAINDICATIONS
`• Known hypersensitivity to product components (4)
`• Active liver disease, which may include unexplained persistent elevations in
`hepatic transaminase levels (4)
`
`• Women who are pregnant or may become pregnant (4, 8.1)
`• Nursing mothers (4, 8.3)
`• Co-administration with cyclosporine (4, 7.1, 12.3)
`
`WARNINGS AND PRECAUTIONS
`• Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks
`increase in a dose-dependent manner, with advanced age (‡65), renal
`impairment, and inadequately treated hypothyroidism. Advise patients to
`promptly report unexplained and/or persistent muscle pain, tenderness, or
`weakness, and discontinue LIVALO (5.1)
`• Liver enzyme abnormalities: Persistent elevations in hepatic
`transaminases can occur. Check liver enzyme tests before initiating therapy
`and as clinically indicated thereafter (5.2)
`
`ADVERSE REACTIONS
`The most frequent adverse reactions (rate ‡2.0% in at least one marketed
`dose) were myalgia, back pain, diarrhea, constipation 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.
`
`To report SUSPECTED ADVERSE REACTIONS, contact at or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch
`
`DRUG INTERACTIONS
`• Erythromycin: Combination increases pitavastatin exposure. Limit
`LIVALO to 1 mg once daily (2.3, 7.2)
`• Rifampin: Combination increases pitavastatin exposure. Limit LIVALO to
`2 mg once daily (2.4, 7.3)
`• Concomitant lipid-lowering therapies: Use with fibrates or lipid-
`modifying doses (‡1 g/day) of niacin increases the risk of adverse skeletal
`muscle effects. Caution should be used when prescribing with LIVALO.
`(5.1, 7.4, 7.5)
`
`USE IN SPECIFIC POPULATIONS
`• Pediatric use: Safety and effectiveness have not been established. (8.4)
`• Renal impairment: Limitation of a starting dose of LIVALO 1 mg once
`daily and a maximum dose of LIVALO 2 mg once daily for patients
`with moderate and severe renal impairment as well as patients receiving
`hemodialysis (2.2, 8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 10/2013
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`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`1 INDICATIONS AND USAGE
`1.1 Primary Hyperlipidemia and Mixed Dyslipidemia
`1.2 Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`2.2 Dosage in Patients with Renal Impairment
`2.3 Use with Erythromycin
`2.4 Use with Rifampin
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Skeletal Muscle Effects
`5.2 Liver Enzyme Abnormalities
`5.3 Endocrine Function
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Cyclosporine
`7.2 Erythromycin
`7.3 Rifampin
`7.4 Gemfibrozil
`7.5 Other Fibrates
`7.6 Niacin
`7.7 Colchicine
`7.8 Warfarin
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Primary Hyperlipidemia or Mixed Dyslipidemia
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Dosing Time
`17.2 Muscle Pain
`17.3 Pregnancy
`17.4 Breastfeeding
`17.5 Liver Enzymes
`
`* Sections or subsections omitted from the full prescribing information are not listed
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`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.
`
`1.1 Primary Hyperlipidemia and Mixed Dyslipidemia
`LIVALO® 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.
`
`1.2 Limitations of Use
`Doses of LIVALO 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 LIVALO.
`The effect of LIVALO on cardiovascular morbidity and mortality has not been determined.
`LIVALO has not been studied in Fredrickson Type I, III, and V dyslipidemias.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`The dose range for LIVALO 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 LIVALO should be individualized according
`to patient characteristics, such as goal of therapy and response.
`After initiation or upon titration of LIVALO, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.
`
`2.2 Dosage in Patients with Renal Impairment
`Patients with moderate and severe renal impairment (glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 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
`LIVALO 1 mg once daily and a maximum dose of LIVALO 2 mg once daily.
`
`2.3 Use with Erythromycin
`In patients taking erythromycin, a dose of LIVALO 1 mg once daily should not be exceeded [see Drug Interactions (7.2)].
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`2.4 Use with Rifampin
`In patients taking rifampin, a dose of LIVALO 2 mg once daily should not be exceeded [see Drug Interactions (7.3)].
`
`3 DOSAGE FORMS AND STRENGTHS
`1 mg: Round white film-coated tablet. Debossed “KC” on one side and “1” on the other side of the tablet.
`2 mg: Round white film-coated tablet. Debossed “KC” on one side and “2” on the other side of the tablet.
`4 mg: Round white film-coated tablet. Debossed “KC” on one side and “4” on the other side of the tablet.
`
`4 CONTRAINDICATIONS
`The use of LIVALO is contraindicated in the following conditions:
`• Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, and
`urticaria have been reported with LIVALO [see Adverse Reactions (6.1)].
`
`• Patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings
`and Precautions (5.2), Use in Specific Populations (8.7)].
`
`• Women who are pregnant or may become pregnant. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and
`possibly the synthesis of other biologically active substances derived from cholesterol, LIVALO may cause fetal harm when
`administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant
`women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the
`potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy [see Use in Specific
`Populations (8.1) and Nonclinical Toxicology (13.2)].
`
`• Nursing mothers. Animal studies have shown that LIVALO passes into breast milk. Since HMG-CoA reductase inhibitors
`have the potential to cause serious adverse reactions in nursing infants, LIVALO, like other HMG-CoA reductase inhibitors, is
`contraindicated in pregnant or nursing mothers [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.2)].
`
`• Co-administration with cyclosporine [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Skeletal Muscle Effects
`Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-
`CoA reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.
`LIVALO 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. LIVALO 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
`(7.6), Use in Specific Populations (8.5, 8.6) and Clinical Pharmacology (12.3)].
`Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with
`colchicine, and caution should be exercised when prescribing LIVALO with colchicine [see Drug Interactions (7.7)].
`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.
`LIVALO therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or
`suspected. LIVALO 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 LIVALO.
`
`5.2 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
`LIVALO. 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, LIVALO 1 mg, or
`LIVALO 2 mg groups. One out of 202 patients (0.5%) administered LIVALO 4 mg had ALT >3 times the upper limit of normal.
`It is recommended that liver enzyme tests be performed before the initiation of LIVALO and if signs or symptoms of liver injury
`occur.
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`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 LIVALO, promptly
`interrupt therapy. If an alternate etiology is not found do not restart LIVALO.
`As with other HMG-CoA reductase inhibitors, LIVALO 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
`LIVALO [see Contraindications (4)].
`
`5.3 Endocrine Function
`Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIVALO.
`
`6 ADVERSE REACTIONS
`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
`(5.1)].
`
`• Liver Enzyme Abnormalities [see Warning and Precautions (5.2)].
`
`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 – 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.
`
`6.1 Clinical Studies Experience
`Because clinical studies on LIVALO are conducted in varying study populations and study designs, the frequency of adverse reactions
`observed in the clinical studies of LIVALO cannot be directly compared with that in the clinical studies of other HMG-CoA reductase
`inhibitors and may not reflect the frequency of adverse reactions observed in clinical 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 ‡2.0% of Patients Treated with LIVALO and > Placebo in Short-Term Controlled Studies
`Adverse
`Placebo
`LIVALO
`LIVALO
`LIVALO
`Reactions*
`N= 208
`1 mg
`2 mg
`4 mg
`N=309
`N=951
`N=1540
`3.9%
`1.8%
`1.4%
`3.6%
`1.5%
`2.2%
`2.6%
`1.5%
`1.9%
`1.9%
`2.8%
`3.1%
`2.3%
`0.6%
`0.9%
`
`2.9%
`Back Pain
`1.9%
`Constipation
`1.9%
`Diarrhea
`1.4%
`Myalgia
`1.9%
`Pain in extremity
`* 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 LIVALO.
`
`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.
`Adverse reactions associated with LIVALO 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 and muscle spasms.
`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).
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`There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions
`(5.1)].
`
`7 DRUG INTERACTIONS
`
`7.1 Cyclosporine
`Cyclosporine significantly increased pitavastatin exposure. Co-administration of cyclosporine with LIVALO is contraindicated [see
`Contraindications (4) and Clinical Pharmacology (12.3)].
`
`7.2 Erythromycin
`Erythromycin significantly increased pitavastatin exposure. In patients taking erythromycin, a dose of LIVALO 1 mg once daily
`should not be exceeded [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
`
`7.3 Rifampin
`Rifampin significantly increased pitavastatin exposure. In patients taking rifampin, a dose of LIVALO 2 mg once daily should not be
`exceeded [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
`
`7.4 Gemfibrozil
`Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil,
`concomitant administration of LIVALO with gemfibrozil should be avoided.
`
`7.5 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, LIVALO should be administered with caution when used concomitantly with other fibrates [see
`Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
`
`7.6 Niacin
`The risk of skeletal muscle effects may be enhanced when LIVALO is used in combination with niacin; a reduction in LIVALO
`dosage should be considered in this setting [see Warnings and Precautions (5.1)].
`
`7.7 Colchicine
`Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with
`colchicine, and caution should be exercised when prescribing LIVALO with colchicine.
`
`7.8 Warfarin
`LIVALO had no significant pharmacokinetic interaction with R- and S- warfarin. LIVALO had no significant effect on prothrombin
`time (PT) and international normalized ratio (INR) when administered to patients receiving chronic warfarin treatment [see Clinical
`Pharmacology (12.3)]. However, patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to
`their therapy.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Teratogenic effects: Pregnancy Category X
`
`LIVALO is contraindicated in women who are or may become pregnant. Serum cholesterol and TG increase during normal
`pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation
`of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy [see
`Contraindications (4)].
`
`There are no adequate and well-controlled studies of LIVALO in pregnant women, although, there have been rare reports of
`congenital anomalies 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. However, this study was
`only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases,
`drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
`
`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.
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`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).
`
`LIVALO may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking LIVALO,
`the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during
`pregnancy.
`
`8.3 Nursing Mothers
`It is not known whether pitavastatin is excreted in human milk, however, it has been shown that a small amount of another drug in this
`class passes into human milk. Rat studies have shown that pitavastatin is excreted into breast milk. Because another drug in this class
`passes into human milk and HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants,
`women who require LIVALO treatment should be advised not to nurse their infants or to discontinue LIVALO [see Contraindications
`(4)].
`
`8.4 Pediatric Use
`Safety and effectiveness of LIVALO in pediatric patients have not been established.
`
`8.5 Geriatric Use
`Of the 2,800 patients randomized to LIVALO 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.
`
`8.6 Renal Impairment
`Patients with moderate and severe renal impairment (glomerular filtration rate 30 – 59 mL/min/1.73 m2 and 15 – 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 LIVALO 1 mg once daily and a maximum dose of LIVALO 2 mg once daily [see Dosage and Administration (2.2) and Clinical
`Pharmacology (12.3)].
`
`8.7 Hepatic Impairment
`LIVALO is contraindicated in patients with active liver disease which may include unexplained persistent elevations of hepatic
`transaminase levels.
`
`10 OVERDOSAGE
`There is no known specific treatment in the event of overdose of pitavastatin. In the event of overdose, the patient should be treated
`symptomatically and supportive measures instituted as required. Hemodialysis is unlikely to be of benefit due to high protein binding
`ratio of pitavastatin.
`
`11 DESCRIPTION
`LIVALO (pitavastatin) is an inhibitor of HMG-CoA reductase. It is a synthetic lipid-lowering agent for oral administration.
`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:
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`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 1.045 mg, 2.09 mg, or 4.18 mg of pitavastatin calcium, which is equivalent to
`1 mg, 2 mg, or 4 mg, respectively of free base and the following inactive ingredients: lactose monohydrate, low substituted
`hydroxypropylcellulose, hypromellose, magnesium aluminometasilicate, magnesium stearate, and film coating containing the
`following inactive ingredients: hypromellose, titanium dioxide, triethyl citrate, and colloidal anhydrous silica.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 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.
`
`12.2 Pharmacodynamics
`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 daily dose).
`
`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 to 24 mg once daily. The absolute
`bioavailability of pitavastatin oral solution is 51%. Administration of LIVALO 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.
`
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`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 LIVALO 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 LIVALO in elderly subjects in
`clinical studies.
`
`Renal Impairment: In patients with moderate renal impairment (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.
`
`In another pharmacokinetic study, patients with severe renal impairment (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%.
`
`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 LIVALO 4 mg daily. However,
`patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.
`
`Table 2. Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure
`Co-administered drug
`Dose regimen
`
`Cyclosporine
`
`Erythromycin
`
`Rifampin
`
`Atazanavir
`
`Darunavir/Ritonavir
`
`Lopinavir/Ritonav