Nikita

Drug Description

What is Nikita and how is it used?

Nikita is used to reduce fats in the blood.

What is Nikita and how is it used?

Common side effects of Nikita include:

• muscle pain,
• back pain,
• diarrhea,
• constipation,
• pain in extremities,
• joint pain,
• headache,
• influenza, and
• runny or stuffy nose.

DESCRIPTION

NIKITA (pitavastatin) is an inhibitor of HMG-CoA reductase. It is a synthetic lipid-lowering agent for oral administration.

The chemical name for pitavastatin is Sodium (3R, 5S, E)-7-(2-cyclopropyl-4-(4-fluorophenyl)­quinolin-3-yl)-3, 5-dihydroxyhept-6-enoate. The structural formula is:

The empirical formula for pitavastatin is C25H23FNO4Na and the molecular weight is 443.15. Pitavastatin occurs as white to pale yellow powder. It is slightly soluble in N, N-Dimethylformamide. Pitavastatin is slightly hygroscopic in nature and slightly unstable in light.

Each film-coated tablet of NIKITA contains 1.052 mg, 2.103 mg, or 4.206 mg of pitavastatin sodium, which is equivalent to 1 mg, 2 mg, or 4 mg, respectively of pitavastatin, and the following inactive ingredients: hypromellose, lactose monohydrate, low substituted hydroxypropylcellulose, magnesium stearate and sodium bicarbonate and film coating containing the following inactive ingredients: colloidal anhydrous silica, hypromellose, titanium dioxide and triethyl citrate.

Indications & Dosage

INDICATIONS

NIKITA is indicated as an adjunctive therapy to diet in:

• Adult patients with primary hyperlipidemia or mixed dyslipidemia 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).

Limitations Of Use

• The effect of NIKITA on cardiovascular morbidity and mortality has not been determined.

Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

DOSAGE AND ADMINISTRATION

General Dosage And Administration Information

• Take NIKITA orally once daily with or without food at the same time each day.
• Individualize the dose of NIKITA according to patient characteristics, goal of therapy, and response.
• After initiation or upon titration of NIKITA, analyze lipid levels after 4 weeks and adjust the dosage accordingly.

Recommended Dosage For Adults

• The recommended starting NIKITA dosage is 2 mg once daily.
• The maximum recommended dosage is NIKITA 4 mg once daily [see WARNINGS AND PRECAUTIONS].

Recommended Dosage In Patients With Renal Impairment

• The recommended starting dose for adults with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 mL/minute/1.73 m² and 15 to 29 mL/minute/1.73 m², respectively) and patients with end-stage renal disease receiving hemodialysis is NIKITA 1 mg once daily.
• The maximum recommended dose for these patients is NIKITA 2 mg once daily [see Use In Specific Populations].

NIKITA Dosage Adjustments Due To Drug Interactions

• In patients taking erythromycin, do not exceed NIKITA 1 mg once daily [see DRUG INTERACTIONS].
• In patients taking rifampin, do not exceed NIKITA 2 mg once daily [see DRUG INTERACTIONS].

Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

HOW SUPPLIED

Dosage Forms And Strengths

Tablets:

• 1 mg: White to off-white, round, film-coated tablet, debossed with “LU” on one side and “C75” on the other side.
• 2 mg: White to off-white, round, film-coated tablet, debossed with “LU” on one side and ‘C76” on the other side.
• 4 mg: White to off-white, round, film-coated tablet, debossed with “LU” on one side and “C77” on the other side.

Storage And Handling

NIKITA tablets are available as follows:

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light.

Manufactured by: Lupin Limited Nagpur 441 108 INDIA. Revised: Sep 2020

Side Effects

The following serious adverse reactions are discussed in other sections of the labeling:

• Myopathy and Rhabdomyolysis [see WARNINGS AND PRECAUTIONS]
• Immune-Mediated Necrotizing Myopathy [see WARNING AND PRECAUTIONS]
• Hepatic Dysfunction [see WARNING AND PRECAUTIONS]
• Increases in HbA1c and Fasting Serum Glucose Levels [see WARNING AND PRECAUTIONS].

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 And Mixed Dyslipidemia

In 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia or mixed dyslipidemia 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 to 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.

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).

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 Adult Patients with Primary Hyperlipidemia and Mixed Dyslipidemia 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 pitavastatin.

The following laboratory abnormalities have been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose.

Adverse Reactions In Adult HIV-Infected Patients With Dyslipidemia

In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either pitavastatin 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 pitavastatin was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with pitavastatin had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with pitavastatin had at least one ALT value exceeding 3 times but less than 5 times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with pitavastatin, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline.

Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pitavastatin. 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

Psychiatric disorders: insomnia, depression. 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).

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic and mediastinal disorders: interstitial lung disease

Drug Interactions

Drug Interactions That Increase The Risk Of Myopathy And Rhabdomyolysis With NIKITA

Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with NIKITA and instructions for preventing or managing drug interactions [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with NIKITA

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Myopathy And Rhabdomyolysis

NIKITA may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including NIKITA.

Risk Factors For Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use of certain drugs, and higher NIKITA dosage. Dosages of pitavastatin greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of NIKITA is 4 mg once daily [see DOSAGE AND ADMINISTRATION].

Steps To Prevent Or Reduce The Risk Of Myopathy And Rhabdomyolysis

NIKITA is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil [see CONTRAINDICATIONS and DRUG INTERACTIONS]. There are NIKITA dosage restrictions for patients taking erythromycin or rifampin [see DOSAGE AND ADMINISTRATION]. The following drugs when used concomitantly with NIKITA may also increase therisk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1grams/day), fibrates, and colchicine [see DRUG INTERACTIONS].

Discontinue NIKITA if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if NIKITA is discontinued. Temporarily discontinue NIKITA in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the NIKITA dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.

Immune-Mediated Necrotizing Myopathy

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; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

Hepatic Dysfunction

Increases in serum transaminases have been reported with NIKITA [see ADVERSE REACTIONS]. In most cases, the elevations were transient and either resolved or improved on continued therapy or after a brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including NIKITA.

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.

Consider liver enzyme testing before the initiation of NIKITA and thereafter, when clinically indicated. NIKITA is contraindicated in patients with active liver disease including unexplained persistent elevations in hepatic transaminase levels [see CONTRAINDICATIONS]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue NIKITA.

Increases In HbA1c And Fasting Serum Glucose Levels

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including NIKITA. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

Nonclinical Toxicology

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 daily, 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 daily 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 daily 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 daily 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.

Use In Specific Populations

Pregnancy

Risk Summary

NIKITA 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 NIKITA during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, NIKITA may cause fetal harm when administered to pregnant women. NIKITA should be discontinued as soon as pregnancy is recognized [see CONTRAINDICATIONS]. Limited published data on the use of pitavastatin 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Limited published data on pitavastatin 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 Data

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.

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).

Lactation

Risk Summary

NIKITA is contraindicated during breastfeeding [see CONTRAINDICATIONS]. 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 NIKITA.

Females And Males Of Reproductive Potential

Contraception

Females

NIKITA may cause fetal harm when administered to a pregnant woman [see Pregnancy]. Advise females of reproductive potential to use effective contraception during treatment with NIKITA.

Pediatric Use

The safety and effectiveness of NIKITA in pediatric patients have not been established.

Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

Geriatric Use

In controlled clinical studies, 1,209 (43%) patients were 65 years and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients.

Advanced age (≥65 years) is a risk factor for myopathy and rhabdomyolysis. In general, dose selection for a geriatric patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy [see WARNINGS AND PRECAUTIONS].

Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Due to the risk of myopathy, a dosage modification of NIKITA is recommended for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 mL/min/1.73 m² and 15 to 29 mL/min/1.73 m², respectively), as well as end-stage renal disease receiving hemodialysis. [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Hepatic Impairment

NIKITA is contraindicated in patients with active liver disease including unexplained persistent elevations of hepatic transaminase levels [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].

Overdosage & Contraindications

OVERDOSE

No specific treatment for NIKITA 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 NIKITA.

CONTRAINDICATIONS

NIKITA is contraindicated in the following conditions:

• Known hypersensitivity to pitavastatin or any inactive ingredient in NIKITA. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with NIKITA [see ADVERSE REACTIONS].
• Concomitant use of cyclosporine [see DRUG INTERACTIONS].
• Active liver disease including unexplained persistent elevations of hepatic transaminase levels [see WARNINGS AND PRECAUTIONS].
• Pregnancy [see Use In Specific Populations].
• 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, females who require pitavastatin treatment should not breastfeed their infants [see Use In Specific Populations].

Clinical Pharmacology

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.

Pharmacodynamics

Cardiac Electrophysiology

In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, pitavastatin 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).

Pharmacokinetics

Absorption

Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0 to inf increased in an approximately dose-proportional manner for single pitavastatin 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 pitavastatin 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. Association of pitavastatin and/or its metabolites with the blood cells is minimal.

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

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 Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.

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.

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]

Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

Patients With Renal Impairment

In adult patients with moderate renal impairment (estimated glomerular filtration rate of 30 to 59 mL/min/1.73 m²) and end stage renal disease receiving hemodialysis, pitavastatin AUC0 to 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].

In another pharmacokinetic study, adult patients with severe renal impairment (estimated glomerular filtration rate 15 to 29 mL/min/1.73 m²) not receiving hemodialysis were administered a single dose of pitavastatin 4 mg. The AUC0 to 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].

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, WARNINGS AND PRECAUTIONS].

Drug Interaction Studies

Warfarin

The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of pitavastatin 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

Animal Toxicology And/Or Pharmacology

Central Nervous System Toxicity

CNS 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).

Clinical Studies

Primary Hyperlipidemia Or Mixed Dyslipidemia In Adult Patients

Active-Controlled Study With Atorvastatin (Study 301)

Pitvastatin was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 817 adult 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 pitavastatin 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, pitavastatin was non-inferior to atorvastatin for the two pairwise comparisons: pitavastatin 2 mg vs. atorvastatin 10 mg and pitavastatin 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 0% (-3%, 3%) and 1% (-2%, 4%), respectively.

Table 5: Lipid Response by Dose of Pitavastatin and Atorvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 301 (Mean % Change from Baseline at Week 12)

Active-Controlled Study With Simvastatin (Study 302)

Pitavastatin was compared with Simvastatin Tablets (referred to as simvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 843 adult 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 pitavastatin 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, pitavastatin was non-inferior to simvastatin for the two pairwise comparisons: pitavastatin 2 mg vs. simvastatin 20 mg and pitavastatin 4 mg vs. simvastatin 40 mg. Mean treatment differences (95% CI) were 4% (1%, 7%) and 1% (-2%, 4%), respectively.

Table 6: Lipid Response by Dose of Pitavastatin and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 302 (Mean % Change from Baseline at Week 12)

Active-Controlled Study With Pravastatin In Geriatric Patients (Study 306)

Pitavastatin was compared with Pravastatin Sodium Tablets (referred to as pravastatin) in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled non-inferiority study of 942 geriatric 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 pitavastatin or pravastatin for 12 weeks (Table 7). Non-inferiority of pitavastatin 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. Pitavastatin significantly reduced LDL-C compared to pravastatin as demonstrated by the following pairwise dose comparisons: pitavastatin 1 mg vs. pravastatin 10 mg, pitavastatin 2 mg vs. pravastatin 20 mg and pitavastatin 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: Lipid Response by Dose of Pitavastatin and Pravastatin in Geriatric Patients with Primary Hyperlipidemia or Mixed Dyslipidemia in Study 306 (Mean % Change from Baseline at Week 12)

Active-Controlled Study With Simvastatin In Patients With ≥ 2 Risk Factors For Coronary Heart Disease (Study 304)

Pitavastatin was compared with Simvastatin Tablets (referred to as simvastatin) in a randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority study of 351 adult 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 pitavastatin or simvastatin (Table 8). Non-inferiority of pitavastatin 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. Pitavastatin 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. Lipid Response by Dose of Pitavastatin and Simvastatin in Adult Patients with Primary Hyperlipidemia or Mixed Dyslipidemia with ≥2 Risk Factors for Coronary Heart Disease in Study 304 (Mean % Change from Baseline at Week 12)

Active-Controlled Study With Atorvastatin In Patients With Type 2 Diabetes Mellitus (Study 305)

Pitavastatin was compared with Atorvastatin Calcium Tablets (referred to as atorvastatin) in a randomized, multicenter, double-blind, double-dummy, parallel group, active-controlled, non-inferiority study of 410 adult patients with type 2 diabetes mellitus and mixed dyslipidemia. Patients entered a 6-to 8-week washout/dietary lead-in period and were randomized to a once daily dose of pitavastatin or atorvastatin for 12 weeks. Non-inferiority of pitavastatin 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. The study failed to demonstrate that pitavastatin was not significantly different than atorvastatin in lowering LDL-C in patients with type 2 diabetes mellitus and mixed dyslipidemia.

Table 9: Lipid Response by Dose of Pitavastatin and Atorvastatin in Adult Patients with Type 2 Diabetes Mellitus and Mixed Dyslipidemia in Study 305 (Mean % Change from Baseline at Week 12)

The treatment differences in efficacy in LDL-C change from baseline between pitavastatin and active controls (i.e., atorvastatin, simvastatin, or pravastatin) in the in the active-controlled studies described above are summarized in Figure 1.

Figure 1: Treatment Difference in Adjusted Mean Percent Change in LDL-C between Pitavastatin and the Comparator (Atorvastatin, Simvastatin, or Pravastatin)

NL=non-inferiority limit.

Pediatric use information is approved for Kowa Co Ltd’s LIVALO (pitavastatin) tablets. However, due to Kowa Co Ltd’s marketing exclusivity rights, this drug product is not labeled with that information.

Medication Guide

PATIENT INFORMATION

The patient should be informed of the following:

Myopathy And Rhabdomyolysis

Advise patients that NIKITA may cause myopathy and rhabdomyolysis. Inform patients that the risk is increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patientsto promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see WARNINGS AND PRECAUTIONS].

Hepatic Dysfunction

Inform patients that NIKITA may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see WARNINGS AND PRECAUTIONS].

Increases In HbA1c And Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with NIKITA. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity

Advise 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, Use In Specific Populations].

Lactation

Advise women not to breastfeed during treatment with NIKITA [see CONTRAINDICATIONS, Use In Specific Populations].