Pitavastatin Calcium KO

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.

Primary Hyperlipidemia And Mixed Dyslipidemia

Pitavastatin Calcium KO^® 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.

Limitations Of Use

Doses of Pitavastatin Calcium KO 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 Pitavastatin Calcium KO.

The effect of Pitavastatin Calcium KO on cardiovascular morbidity and mortality has not been determined.

Pitavastatin Calcium KO has not been studied in Fredrickson Type I, III, and V dyslipidemias.

General Dosing Information

The dose range for Pitavastatin Calcium KO 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 Pitavastatin Calcium KO should be individualized according to patient characteristics, such as goal of therapy and response.

After initiation or upon titration of Pitavastatin Calcium KO, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.

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 Pitavastatin Calcium KO 1 mg once daily and a maximum dose of Pitavastatin Calcium KO 2 mg once daily.

Use With Erythromycin

In patients taking erythromycin, a dose of Pitavastatin Calcium KO 1 mg once daily should not be exceeded.

Use With Rifampin

In patients taking rifampin, a dose of Pitavastatin Calcium KO 2 mg once daily should not be exceeded.

The use of Pitavastatin Calcium KO 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 Pitavastatin Calcium KO.
• Patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.
• Co-administration with cyclosporine.
• Pregnancy..
• 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.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Pitavastatin Calcium KO. These risks can occur at any dose level, but increase in a dose-dependent manner.

Pitavastatin Calcium KO 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. Pitavastatin Calcium KO 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.

Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing Pitavastatin Calcium KO with colchicine.

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.

Pitavastatin Calcium KO therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Pitavastatin Calcium KO 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 Pitavastatin Calcium KO.

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 Pitavastatin Calcium KO. 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, Pitavastatin Calcium KO 1 mg, or Pitavastatin Calcium KO 2 mg groups. One out of 202 patients (0.5%) administered Pitavastatin Calcium KO 4 mg had ALT >3 times the upper limit of normal.

It is recommended that liver enzyme tests be performed before the initiation of Pitavastatin Calcium KO 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 Pitavastatin Calcium KO, promptly interrupt therapy. If an alternate etiology is not found do not restart Pitavastatin Calcium KO.

As with other HMG-CoA reductase inhibitors, Pitavastatin Calcium KO 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 Pitavastatin Calcium KO.

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Pitavastatin Calcium KO.

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/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.

Use In Specific Populations

Pregnancy

Risk Summary

Pitavastatin Calcium KO 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 Pitavastatin Calcium KO during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Pitavastatin Calcium KO may cause fetal harm when administered to pregnant women. Pitavastatin Calcium KO should be discontinued as soon as pregnancy is recognized. Limited published data on the use of Pitavastatin Calcium KO 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).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Limited published data on Pitavastatin Calcium KO 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

Pitavastatin Calcium KO is contraindicated during breastfeeding. 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 Pitavastatin Calcium KO.

Females And Males Of Reproductive Potential

Contraception

Females

Pitavastatin Calcium KO may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Pitavastatin Calcium KO.

Pediatric Use

Safety and effectiveness of Pitavastatin Calcium KO in pediatric patients have not been established.

Geriatric Use

Of the 2,800 patients randomized to Pitavastatin Calcium KO 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.

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 Pitavastatin Calcium KO 1 mg once daily and a maximum dose of Pitavastatin Calcium KO 2 mg once daily.

Hepatic Impairment

Pitavastatin Calcium KO is contraindicated in patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.

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).
• Liver Enzyme Abnormalities.

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.

Clinical Studies Experience

Because clinical studies on Pitavastatin Calcium KO are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of Pitavastatin Calcium KO 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 Pitavastatin Calcium KO and >Placebo in Short-Term Controlled Studies

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 Pitavastatin Calcium KO.

In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either Pitavastatin Calcium KO 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 Pitavastatin Calcium KO was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with Pitavastatin Calcium KO had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (10x ULN), which resolved spontaneously. Four patients (3%) treated with Pitavastatin Calcium KO 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 Pitavastatin Calcium KO, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Pitavastatin Calcium KO. 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 Pitavastatin Calcium KO 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.

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.

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

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 Pitavastatin Calcium KO doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of Pitavastatin Calcium KO 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 Pitavastatin Calcium KO 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 Pitavastatin Calcium KO 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 Pitavastatin Calcium KO 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.