2.1 Important Dosage and Administration Information

• Take NIKITA orally once daily with or without food at the same time each day.
• For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving NIKITA 4 mg daily, prescribe alternative LDL-C-lowering treatment.
• Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating NIKITA, and adjust the dosage if necessary.

2.2 Recommended Dosage for Adults

• The recommended dosage range of NIKITA is 2 mg to 4 mg daily.
• The maximum recommended dosage is NIKITA 4 mg once daily.

2.3 Recommended Dosage in Patients with Renal Impairment

• The recommended starting dosage for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 mL/minute/1.73 m2and 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 (8.5)].
• There are no dosage adjustment recommendations for patients with mild renal impairment.

2.4 Dosage Modifications Due to Drug Interactions

• In patients taking erythromycin, do not exceed NIKITA 1 mg once daily [see Drug Interactions (7)] .
• In patients taking rifampin, do not exceed NIKITA 2 mg once daily [see Drug Interactions (7)] .

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

5.1 Myopathy and Rhabdomyolysis

NIKITA may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) above ten times the upper limit of normal) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, 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 (including other lipid-lowering therapies), and higher NIKITA dosage [see Dosage and Administration (2.2), Drug Interactions (7), and Use in Specific Populations (8.5, 8.6)]. 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.

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 (4) and Drug Interactions (7)]. There are NIKITA dosage restrictions for patients taking erythromycin or rifampin [see Dosage and Administration (2.4)]. The following drugs when used concomitantly with NIKITA may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1grams/day), fibrates, and colchicine [see Drug Interactions (7)].

Discontinue NIKITA if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations 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.

5.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that 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. Discontinue NIKITA if IMNM is suspected.

5.3 Hepatic Dysfunction

Increases in serum transaminases have been reported with NIKITA [see Adverse Reactions (6)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and 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 when clinically indicated thereafter. NIKITA is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue NIKITA. 

5.4 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.

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of one drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Adults with Primary Hyperlipidemia

In 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia were administered pitavastatin 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 52% were females. Approximately 93% of the patients were White, 7% were Asian/Indian, 0.2% were African American and 0.3% were Hispanic and other.

In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin-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. 

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.

6.2 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

Skin and subcutaneous tissue disorders: lichen planus

8.1 Pregnancy

Risk Summary

Discontinue NIKITA when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient.

NIKITA decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, NIKITA may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.

Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with statin use in pregnant women are insufficient to determine if there is a drug associated risk of miscarriage (see Data).

In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed in pregnant rats and rabbits orally administered pitavastatin during the period of organogenesis at doses which were 22 and 4 times, respectively, the human exposure at the maximum recommended human dosage (MRHD) of 4 mg, based on AUC [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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:

A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

Animal Data:

Embryo-fetal developmental studies were conducted in pregnant rats administered 3, 10, 30 mg/kg/day pitavastatin by oral gavage during organogenesis (gestation days 7-17).  No adverse effects were observed at 3 mg/kg/day, systemic exposures 22 times human systemic exposure at 4 mg/day based on AUC.  

Embryo-fetal developmental studies were conducted in pregnant rabbits administered 0.1, 0.3, 1 mg/kg/day pitavastatin by oral gavage during the period of fetal organogenesis (gestation days 6-18).  Maternal toxicity consisting of reduced body weight and abortion was observed at all doses tested (4 times human systemic exposure at 4 mg/day based on AUC).

In perinatal/postnatal studies in pregnant rats given oral gavage doses of pitavastatin at 0.1, 0.3, 1, 3, 10, 30 mg/kg/day from organogenesis through weaning (gestation day 17 to lactation day 21), maternal toxicity consisting of mortality at ≥0.3 mg/kg/day and impaired lactation at all doses contributed to the decreased survival of neonates in all dose groups (0.1 mg/kg/day represents approximately 1 time human systemic exposure at 4 mg/day dose based on AUC).

Reproductive toxicity studies have shown that pitavastatin crosses the placenta in rats and is found in fetal tissues at ≤36% of maternal plasma concentrations following a single dose of 1 mg/kg/day during gestation (at the end of organogenesis).

8.2 Lactation

Risk Summary

There is no available information about the prescence of pitavastatin in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Statins, including NIKITA, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

Because of the potential for serious adverse reactions in a breastfed infant, based upon the mechanism of action, advise patients that breastfeeding is not recommended during treatment with NIKITA. [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)]

8.4 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.

8.5 Geriatric Use

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

Advanced age (≥65 years) is a risk factor for NIKITA-associated myopathy and rhabdomyolysis. Dose selection for a geriatric patient should be cautious, reognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving NIKITA for the increased risk of myopathy [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Due to the risk of myopathy, a dosage modification of NIKITA is recommended for patients with moderate and severe renal impairment (estimated glomerular filtration rate 30 to 59 mL/min/1.73 m2and 15 to 29 mL/min/1.73 m2, respectively), as well as end-stage renal disease receiving hemodialysis. [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

NIKITA is contraindicated in patients with active liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

12.1 Mechanism of Action

Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the biosynthetic pathway for cholesterol. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma TC decreases. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low density lipoproteins. 

12.2 Pharmacodynamics

Cardiac Electrophysiology 

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

12.3 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.

Elimination 

Metabolism 

The principal route of pitavastatin metabolism is glucuronidation via liver uridine 5'-diphosphate glucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone, which is formed via an ester-type pitavastatin glucuronide conjugate by UGTs (UGT1A3 and UGT2B7).  

Excretion 

A mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours. 

Specific Populations

Geriatric Patients 

In a pharmacokinetic study which compared healthy young and geriatric (≥65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the geriatric patients [see Use in Specific Populations (8.4)]  

Pediatric 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. 

Male and Female Patients

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

Racial or Ethnic Groups

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

Patients with Renal Impairment

In 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 (8.5)]. 

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 (8.5)].

The effect of mild renal impairment on pitavastatin exposure has not been studied.   

Patients with Hepatic Impairment  

The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. Pitavastatin Cmax and AUCinf in patients with moderate hepatic impairment (Child-Pugh B disease) was 2.7-fold and 3.8-fold higher, respectively as compared to healthy volunteers. In patients with mild hepatic impairment (Child-Pugh A disease), pitavastatin Cmax and AUCinf were 30% and 60% higher as compared to healthy volunteers. Mean pitavastatin half-life for moderate hepatic impairment, mild hepatic impairment, and healthy volunteers were 15, 10, and 8 hours, respectively [see Contraindications (4), Warnings and Precautions (5.3)].  

Drug Interaction Studies

Warfarin

The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the coadministration of pitavastatin 4 mg daily. 

Table 3 presents the effect of coadministered drugs on pitavastatin systemic exposure:

*Data presented as x-fold change represent the ratio between coadministration 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 (2.4), Drug Interactions (7)] BID = twice daily; QD = once daily; LA = Long Acting

Table 4 presents the effect of pitavastatin coadministration on systemic exposure of 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 Acting

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 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.