NDC 66869-104 Livalo

Pitavastatin Calcium

NDC Product Code 66869-104

NDC Code: 66869-104

Proprietary Name: Livalo What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Pitavastatin Calcium What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE)
Shape: ROUND (C48348)
Size(s):
6 MM
Imprint(s):
1;KC
Score: 1

NDC Code Structure

  • 66869 - Kowa Pharmaceuticals America, Inc.
    • 66869-104 - Livalo

NDC 66869-104-90

Package Description: 90 TABLET, FILM COATED in 1 BOTTLE, DISPENSING

NDC Product Information

Livalo with NDC 66869-104 is a a human prescription drug product labeled by Kowa Pharmaceuticals America, Inc.. The generic name of Livalo is pitavastatin calcium. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Kowa Pharmaceuticals America, Inc.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Livalo Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • PITAVASTATIN CALCIUM 1.045 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • MAGNESIUM ALUMINOMETASILICATE TYPE I-B (UNII: 8XK1039013)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors - [MoA] (Mechanism of Action)
  • HMG-CoA Reductase Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Kowa Pharmaceuticals America, Inc.
Labeler Code: 66869
FDA Application Number: NDA022363 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-16-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Pitavastatin

Pitavastatin is pronounced as (pit a'' va stat' in)

Why is pitavastatin medication prescribed?
Pitavastatin is used together with diet, weight-loss, and exercise to reduce the amount of fatty substances such as low-density lipoprotein (LDL) cholesterol ('bad choles...
[Read More]

* Please review the disclaimer below.

Livalo Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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.

2.1 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)].

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)].Co-administration with cyclosporine [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].Pregnancy. [see Use in Specific Populations (8.1, 8.3)].Lactation. It is not known if pitavastatin is present in human milk; however, another drug in this class passes into breast milk. Since HMG-CoA reductase inhibitors have the potential for serious adverse reactions in breastfed infants, women who require pitavastatin treatment should not breastfeed their infants [see Use in Specific Populations (8.2)].

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.
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 reactions by MedDRA preferred term.AdverseReactions*PlaceboN= 208LIVALO1 mgN=309LIVALO2 mgN=951LIVALO4 mgN=1540Back Pain2.9%3.9%1.8%1.4%Constipation1.9%3.6%1.5%2.2%Diarrhea1.9%2.6%1.5%1.9%Myalgia1.4%1.9%2.8%3.1%Pain in extremity1.9%2.3%0.6%0.9%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.In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either LIVALO 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 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 (10x ULN), which resolved spontaneously. Four patients (3%) treated with LIVALO had at least one ALT value exceeding 3x but less than 5x ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with 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.

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, muscle spasms and peripheral neuropathy.There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].

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.

8.1 Pregnancy

Risk SummaryLIVALO is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with LIVALO during pregnancy. 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. LIVALO should be discontinued as soon as pregnancy is recognized [see Contraindications (4). Limited published data on the use of LIVALO are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed when pregnant rats and rabbits were orally administered pitavastatin during organogenesis at exposures which were 22 and 4 times, respectively, the maximum recommended human dose (MRHD) [see Data].The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human DataLimited published data on LIVALO have not reported a drug-associated risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate to exclude a greater than or equal to a 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.Animal DataReproductive toxicity studies have shown that pitavastatin crosses the placenta in rats and is found in fetal tissues at ≤36% of maternal plasma concentrations following a single dose of 1 mg/kg/day during gestation.Embryo-fetal developmental studies were conducted in pregnant rats treated with 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis. No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC.Embryo-fetal developmental studies were conducted in pregnant rabbits treated with 0.1, 0.3, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis. Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at 4 mg/day based on AUC).In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning, maternal toxicity consisting of mortality at ≥0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups (0.1 mg/kg/day represents approximately 1 time human systemic exposure at 4 mg/day dose based on AUC).

8.2 Lactation

Risk SummaryLIVALO is contraindicated during breastfeeding [see Contraindications (4)] . There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with LIVALO.

8.3 Females And Males Of Reproductive Potential

ContraceptionFemalesLIVALO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with LIVALO.

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: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.

12.1 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).

Other

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.

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 *Data presented as x-fold change represent the ratio between co-administration and pitavastatin alone (i.e., 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (i.e., 0% = no change).† Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)]BID = twice daily; QD = once daily; LA = Long ActingCo-administered drugDose regimenChange inAUC*Change in Cmax*CyclosporinePitavastatin 2 mg QD for 6 days + cyclosporine 2 mg/kg on Day 6↑ 4.6 fold†↑ 6.6 fold †ErythromycinPitavastatin 4 mg single dose on Day 4 + erythromycin 500 mg 4 times daily for 6 days↑ 2.8 fold †↑ 3.6 fold †RifampinPitavastatin 4 mg QD + rifampin 600 mg QD for 5 days↑ 29%↑ 2.0 foldAtazanavirPitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days↑ 31%↑ 60%Darunavir/RitonavirPitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16↓ 26%↓ 4%Lopinavir/RitonavirPitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24↓ 20%↓4 %GemfibrozilPitavastatin 4 mg QD + gemfibrozil 600 mg BID for 7 days↑ 45%↑ 31%FenofibratePitavastatin 4 mg QD + fenofibrate 160 mg QD for 7 days↑18%↑ 11%EzetimibePitavastatin 2 mg QD + ezetimibe 10 mg for 7 days↓ 2%↓0.2%EnalaprilPitavastatin 4 mg QD + enalapril 20 mg daily for 5 days↑ 6%↓ 7%DigoxinPitavastatin 4 mg QD + digoxin 0.25 mg for 7 days↑ 4%↓ 9%Diltiazem LAPitavastatin 4 mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15↑10%↑15%Grapefruit JuicePitavastatin 2 mg single dose on Day 3 + grapefruit juice for 4 days↑ 15%↓ 12%ItraconazolePitavastatin 4 mg single dose on Day 4 + itraconazole 200 mg daily for 5 days↓ 23%↓ 22%Table 3. Effect of Pitavastatin Co-Administration on Systemic Exposure to Other Drugs *Data presented as % change represent % difference relative to the investigated drug alone (i.e., 0% = no change).BID = twice daily; QD = once daily; LA = Long ActingCo-administered drugDose regimenChange inAUC*Change in Cmax*AtazanavirPitavastatin 4 mg QD + atazanavir 300 mg daily for 5 days↑ 6%↑ 13%DarunavirPitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16↑ 3%↑ 6%LopinavirPitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24↓ 9%↓ 7%RitonavirPitavastatin 4 mg QD on Days 1-5 and 20-24 + lopinavir/ritonavir 400 mg/100 mg BID on Days 9 – 24↓ 11%↓ 11%RitonavirPitavastatin 4mg QD on Days 1-5 and 12-16 + darunavir/ritonavir 800mg/100 mg QD on Days 6-16↑ 8%↑ 2%EnalaprilPitavastatin 4 mg QD + enalapril 20 mgdaily for 5 daysEnalapril↑ 12%↑ 12%Enalaprilat↓ 1%↓ 1%WarfarinIndividualized maintenance dose of warfarin (2 - 7 mg) for 8 days + pitavastatin 4 mg QD for 9 daysR-warfarin↑ 7%↑ 3%S-warfarin↑ 6%↑ 3%EzetimibePitavastatin 2 mg QD + ezetimibe 10 mg for 7 days↑ 9%↑ 2%DigoxinPitavastatin 4 mg QD + digoxin 0.25 mg for 7 days↓ 3%↓ 4%Diltiazem LAPitavastatin 4 mg QD on Days 1-5 and 11-15 and diltiazem LA 240 mg on Days 6-15↓ 2%↓ 7%RifampinPitavastatin 4 mg QD + rifampin 600 mg QD for 5 days↓ 15%↓ 18%

Central Nervous System ToxicityCNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Wallerian degeneration has not been observed with pitavastatin. Cataracts and lens opacities were seen in dogs treated for 52 weeks at a dose level of 1 mg/kg/day (9 times clinical exposure at the maximum human dose of 4 mg/day based on AUC comparisons).

Dose-ranging study: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was performed to evaluate the efficacy of LIVALO compared with placebo in 251 patients with primary hyperlipidemia (Table 4). LIVALO given as a single daily dose for 12 weeks significantly reduced plasma LDL-C, TC, TG, and Apo-B compared to placebo and was associated with variable increases in HDL-C across the dose range.Table 4. Dose-Response in Patients with Primary Hypercholesterolemia (Adjusted Mean % Change from Baseline at Week 12) # The number of subjects for Apo-B was 49TreatmentNLDL-CApo-BTCTGHDL-CPlacebo53-3-2-210LIVALO 1mg52-32-25-23-158LIVALO 2mg49-36-30-26-197LIVALO 4mg51#-43-35-31-185

Active-controlled study with atorvastatin (NK-104-301): LIVALO was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 817 patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12-week treatment with either LIVALO or atorvastatin (Table 5). Non-inferiority of pitavastatin to a given dose of atorvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.Lipid results are shown in Table 5. For the percent change from baseline to endpoint in LDL-C, LIVALO was non-inferior to atorvastatin for the two pairwise comparisons: LIVALO 2 mg vs. atorvastatin 10 mg and LIVALO 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.Table 5. Response by Dose of LIVALO and Atorvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12) TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO2 mg daily315-38-30-28-144-35LIVALO 4 mg daily298-45-35-32-195-41Atorvastatin 10 mg daily102-38-29-28-183-35Atorvastatin 20 mg daily102-44-36-33-222-41Atorvastatin40 mg dailyAtorvastatin80 mg daily-----------------------------------------Not Studied--------------------------------------------------------------------------------------------------Not Studied---------------------------------------------------------

Active-controlled study with simvastatin (NK-104-302): LIVALO was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 843 patients with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period and then were randomized to a 12 week treatment with either LIVALO or simvastatin (Table 6). Non-inferiority of pitavastatin to a given dose of simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.Lipid results are shown in Table 6. For the percent change from baseline to endpoint in LDL-C, LIVALO was non-inferior to simvastatin for the two pairwise comparisons: LIVALO 2 mg vs. simvastatin 20 mg and LIVALO 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.Table 6. Response by Dose of LIVALO and Simvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12) TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO2 mg daily307-39-30-28-166-36LIVALO4 mg daily319-44-35-32-176-41Simvastatin 20 mg daily107-35-27-25-166-32Simvastatin 40 mg daily110-43-34-31-167-39Simvastatin80 mg---------------------------------------Not Studied------------------------------------------------------------

Active-controlled study with pravastatin in elderly (NK-104-306): LIVALO was compared with the HMG-CoA reductase inhibitor pravastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority Phase 3 study of 942 elderly patients (≥65 years) with primary hyperlipidemia or mixed dyslipidemia. Patients entered a 6- to 8-week wash-out/dietary lead-in period, and then were randomized to a once daily dose of LIVALO or pravastatin for 12 weeks (Table 7). Non-inferiority of LIVALO to a given dose of pravastatin was assumed if the lower bound of the 95% CI for the treatment difference was greater than -6% for the mean percent change in LDL-C.
Lipid results are shown in Table 7. LIVALO significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: LIVALO 1 mg vs. pravastatin 10 mg, LIVALO 2 mg vs. pravastatin 20 mg and LIVALO 4 mg vs. pravastatin 40 mg. Mean treatment differences (95% CI) were 9% (6%, 12%), 10% (7%, 13%) and 10% (7%, 13% ), respectively.
Table 7. Response by Dose of LIVALO and Pravastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia (Mean % Change from Baseline at Week 12)
Treatment
N
LDL-C
Apo-B
TC
TG
HDL-C
non-HDL-C
LIVALO1 mg daily
207
-31
-25
-22
-13
1
-29
LIVALO2 mg daily
224
-39
-31
-27
-15
2
-36
LIVALO 4 mg daily
210
-44
-37
-31
-22
4
-41
Pravastatin 10 mg daily
103
-22
-17
-15
-5
0
-20
Pravastatin 20 mg daily
96
-29
-22
-21
-11
-1
-27
Pravastatin 40 mg daily
102
-34
-28
-24
-15
1
-32
Pravastatin80 mg daily
--------------------------------------Not Studied------------------------------------------------------------

Active-controlled study with simvastatin in patients with ≥ 2 risk factors for coronary heart disease (NK-104-304): LIVALO was compared with the HMG-CoA reductase inhibitor simvastatin in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority Phase 3 study of 351 patients with primary hyperlipidemia or mixed dyslipidemia with ≥2 risk factors for coronary heart disease. After a 6- to 8-week wash-out/dietary lead-in period, patients were randomized to a 12-week treatment with either LIVALO or simvastatin (Table 8). Non-inferiority of LIVALO to simvastatin was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.
Lipid results are shown in Table 8. LIVALO 4 mg was non-inferior to simvastatin 40 mg for percent change from baseline to endpoint in LDL-C. The mean treatment difference (95% CI) was 0% (-2%, 3%).
Table 8. Response by Dose of LIVALO and Simvastatin in Patients with Primary Hyperlipidemia or Mixed Dyslipidemia with ≥2 Risk Factors for Coronary Heart Disease (Mean % Change from Baseline at Week 12)
Treatment
N
LDL-C
Apo-B
TC
TG
HDL-C
non-HDL-C
LIVALO4 mg daily
233
-44
-34
-31
-20
7
-40
Simvastatin 40 mg daily
118
-44
-34
-31
-15
5
-39
Simvastatin80 mg daily
--------------------------------------Not Studied--------------------------------------------------------------

Active-controlled study with atorvastatin in patients with type II diabetes mellitus (NK-104-305): LIVALO was compared with the HMG-CoA reductase inhibitor atorvastatin in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority Phase 3 study of 410 subjects with type II diabetes mellitus and combined dyslipidemia. Patients entered a 6- to 8-week washout/dietary lead-in period and were randomized to a once daily dose of LIVALO or atorvastatin for 12 weeks. Non-inferiority of LIVALO was considered to be demonstrated if the lower bound of the 95% CI for the mean treatment difference was greater than -6% for the mean percent change in LDL-C.Lipid results are shown in Table 9. The treatment difference (95% CI) for LDL-C percent change from baseline was -2% (-6.2%, 1.5%). The two treatment groups were not statistically different on LDL-C. However, the lower limit of the CI was -6.2%, slightly exceeding the -6% non-inferiority limit so that the non-inferiority objective was not achieved.Table 9. Response by Dose of LIVALO and Atorvastatin in Patients with Type II Diabetes Mellitus and Combined Dyslipidemia (Mean % Change from Baseline at Week 12) TreatmentNLDL-CApo-BTCTGHDL-Cnon-HDL-CLIVALO4 mg daily274-41-32-28-207-36Atorvastatin20 mg daily136-43-34-32-278-40Atorvastatin 40 mg daily-----------------------------------Not Studied----------------------------------------------------------Atorvastatin 80 mg daily-----------------------------------Not Studied----------------------------------------------------------The treatment differences in efficacy in LDL-C change from baseline between LIVALO and active controls in the Phase 3 studies are summarized in Figure 1.Figure 1. Treatment Difference in Adjusted Mean Percent Change in LDL-C

  • PackagingLIVALO (pitavastatin) Tablets are supplied as;
  • NDC 66869-104-90 : 1 mg. Round white film-coated tablet debossed “KC” on one face and “1” on the reverse; HDPE bottles of 90 tablets
  • NDC 66869-204-90 : 2 mg. Round white film-coated tablet debossed “KC” on one face and “2” on the reverse; HDPE bottles of 90 tablets
  • NDC 66869-404-90 : 4 mg. Round white film-coated tablet debossed “KC” on one face and “4” on the reverse; HDPE bottles of 90 tablets

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 92-week carcinogenicity study in mice given pitavastatin, at the maximum tolerated dose of 75 mg/kg/day with systemic maximum exposures (AUC) 26 times the clinical maximum exposure at 4 mg/day, there was an absence of drug-related tumors.
In a 92-week carcinogenicity study in rats given pitavastatin at 1, 5, 25 mg/kg/day by oral gavage there was a significant increase in the incidence of thyroid follicular cell tumors at 25 mg/kg/day, which represents 295 times human systemic exposures based on AUC at the 4 mg/day maximum human dose.
In a 26-week transgenic mouse (Tg rasH2) carcinogenicity study where animals were given pitavastatin at 30, 75, and 150 mg/kg/day by oral gavage, no clinically significant tumors were observed.
Pitavastatin was not mutagenic in the Ames test with Salmonella typhimurium and Escherichia coli with and without metabolic activation, the micronucleus test following a single administration in mice and multiple administrations in rats, the unscheduled DNA synthesis test in rats, and a Comet assay in mice. In the chromosomal aberration test, clastogenicity was observed at the highest doses tested which also elicited high levels of cytotoxicity.
Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg/day, respectively, at systemic exposures 56- and 354-times clinical exposure at 4 mg/day based on AUC.
Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg/day (30-times clinical systemic exposure at 4 mg/day based on AUC) and higher during a fertility study. Although the cause of death was not determined, rabbits had gross signs of renal toxicity (kidneys whitened) indicative of possible ischemia. Lower doses (15-times human systemic exposure) did not show significant toxicity in adult males and females. However, decreased implantations, increased resorptions, and decreased viability of fetuses were observed.

16 How Supplied/Storage And Handling

LIVALO tablets for oral administration are provided as white, film-coated tablets that contain 1 mg, 2 mg, or 4 mg of pitavastatin. Each tablet has “KC” debossed on one side and a code number specific to the tablet strength on the other.

Storage And Handling

StorageStore at room temperature between 15°C and 30°C (59° to 86° F) [see USP]. Protect from light.

17 Patient Counseling Information

The patient should be informed of the following:Dosing TimeLIVALO can be taken at any time of the day with or without food.Muscle PainPatients should be advised to promptly notify their physician of any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever, or if these muscle signs or symptoms persist after discontinuing LIVALO. They should discuss all medication, both prescription and over the counter, with their physician.Embryo-fetal ToxicityAdvise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment and to inform their healthcare professional of a known or suspected pregnancy [see Contraindications (4), Use in Specific Populations (8.1, 8.3)].LactationAdvise women not to breastfeed during treatment with LIVALO [see Contraindications (4), Use in Specific Populations (8.2)].Liver EnzymesIt is recommended that liver enzyme tests be checked before the initiation of LIVALO and if signs or symptoms of liver injury occur. All patients treated with LIVALO should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.LIVALO is a trademark of the Kowa group of companies.© Kowa Pharmaceuticals America, Inc. (2009)Manufactured under license from: Kowa Company, Limited Tokyo 103-8433 JapanProduct of JapanManufactured into tablets by: Patheon, Inc. Cincinnati, OH 45237 USA or by Kowa Company, LTD Nagoya, 462-0024 JapanMarketed by: Kowa Pharmaceuticals America, Inc. Montgomery, AL 36117 USATo request additional information or if you have questions concerning LIVALO please phone Kowa Pharmaceuticals America, Inc. at 877-8-LIVALO (877-854-8256) or fax your inquiry to 800-689-0244

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