Pitavastatin Calcium

Class: HMG-CoA Reductase Inhibitors
VA Class: CV350
Molecular Formula: C₅₀H₄₆CaF₂N₂O₈
Brands: Livalo

Introduction

Antilipemic agent; hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin).¹

Uses for Pitavastatin Calcium

Dyslipidemias

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the management of primary hypercholesterolemia or mixed dyslipidemia.¹

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Reductions in LDL-cholesterol concentrations achieved with usual dosages (1–4 mg daily) of pitavastatin are similar to or greater than those achieved with low to medium dosages of certain other statins (i.e., atorvastatin, pravastatin, simvastatin).^{1 3 4 5 9}

Safety and efficacy not established in patients with Fredrickson type I, III, or V dyslipidemia.¹ Effect on cardiovascular morbidity and mortality not established.¹

Pitavastatin Calcium Dosage and Administration

General

• Patients should be placed on a standard lipid-lowering diet before initiation of pitavastatin therapy and should remain on this diet during treatment with the drug.¹

Monitoring during Antilipemic Therapy

• Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.³²

Administration

Oral Administration

Administer orally once daily at any time of day, without regard to food.¹

Dosage

Available as pitavastatin calcium; dosage expressed in terms of pitavastatin.¹

Adults

Dyslipidemias

Primary Hypercholesterolemia or Mixed Dyslipidemia

Oral

Initially, 2 mg once daily.¹ Determine serum lipoprotein concentrations 4 weeks after initiating or titrating therapy and adjust dosage accordingly.¹ Usual maintenance dosage is 1–4 mg once daily.¹

Prescribing Limits

Adults

Dyslipidemias

Primary Hypercholesterolemia or Mixed Dyslipidemia

Oral

Maximum 4 mg once daily.¹

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹ (See Contraindications under Cautions, and also see Absorption: Special Populations and see Elimination: Special Populations under Pharmacokinetics.)

Renal Impairment

Moderate to severe renal impairment (GFR 15–59 mL/minute per 1.73 m², not undergoing hemodialysis): Initially, 1 mg once daily.¹ Maximum 2 mg once daily.¹

End-stage renal disease (ESRD) requiring hemodialysis: Initially, 1 mg once daily.¹ Maximum 2 mg once daily.¹

Geriatric Patients

No specific dosage recommendations at this time.¹ (See Geriatric Use under Cautions.)

Cautions for Pitavastatin Calcium

Contraindications

• Active liver disease, including unexplained, persistent elevations of serum aminotransferase concentrations.¹

• Pregnancy or lactation.¹ (See Lactation and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Concomitant use with cyclosporine.¹ (See Specific Drugs and Foods under Interactions.)

• Known hypersensitivity to pitavastatin or any ingredient in the formulation.¹ (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis by pitavastatin could cause fetal harm.¹ Congenital anomalies following intrauterine exposure to statins reported rarely.¹

Advise women of childbearing potential to use effective contraceptive methods during pitavastatin therapy.¹ If the patient becomes pregnant while taking the drug, discontinue therapy and apprise patient of potential fetal hazard and the lack of known clinical benefit with continued use during pregnancy.¹

Musculoskeletal Effects

Myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria reported.¹ May occur at any dosage, but risk increases with increasing dosage; in clinical studies, risk of severe myopathy increased with dosages >4 mg daily.¹

Use with caution in patients with predisposing factors for myopathy (e.g., age >65 years, renal impairment, inadequately treated hypothyroidism) and in patients receiving concomitant therapy with certain antilipemic agents (i.e., fibric acid derivatives, niacin).¹ (See Interactions.)

Discontinue if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.¹

Temporarily withhold therapy in patients experiencing 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, or electrolyte disorders; uncontrolled seizures). (See Advice to Patients.)¹

Hepatic Effects

Increases in serum aminotransferase (i.e., AST, ALT) concentrations reported.¹ Increases usually transient and resolve or improve with continued therapy or after temporary interruption of therapy.¹ Increases in alkaline phosphatase and bilirubin concentrations also reported.¹

Fatal and nonfatal hepatic failure reported rarely.¹

Perform liver function tests prior to initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage²⁰¹ ).¹ Although manufacturer previously recommended more frequent monitoring, FDA concluded that serious statin-related liver injury with statins is rare and unpredictable, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.²⁰⁰

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt pitavastatin therapy.¹ If an alternate etiology is not found, do not restart pitavastatin.¹

Also see Hepatic Impairment under Cautions.

Hyperglycemic Effects

Increases in HbA_1c and fasting serum glucose concentrations reported.^{1 200} Possible increased risk of developing diabetes.²⁰⁰ May need to monitor glucose concentrations following initiation of statin therapy.²⁰¹

FDA states that cardiovascular benefits of statins outweigh these small increased risks.²⁰⁰

Sensitivity Reactions

Hypersensitivity reactions, including rash, pruritus, and urticaria, reported.¹

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) reported rarely.¹

Generally nonserious and reversible, with variable times to symptom onset (1 day to years) and resolution (median of 3 weeks following discontinuance of therapy).^{1 200} Not associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or clinically important cognitive decline.²⁰⁰ Not associated with any specific statin, patient's age, statin dosage, or concomitant drug therapy.²⁰⁰

FDA states that cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment.²⁰⁰

If manifestations consistent with cognitive impairment occur, National Lipid Association (NLA) statin safety assessment task force recommends evaluating and managing patients appropriately.²⁰²

Specific Populations

Pregnancy

Category X.¹ (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats.¹ Not known whether distributed into human milk; however, a small amount of another statin is distributed into human milk.¹ Use is contraindicated; discontinue nursing or pitavastatin.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.^{1 29}

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Contraindicated in patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.¹ (See Absorption: Special Populations and also Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Dosage adjustments necessary in patients with moderate or severe renal impairment and patients with ESRD undergoing hemodialysis.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Myalgia, back pain, diarrhea, constipation, pain in extremity.¹

Interactions for Pitavastatin Calcium

Minimally metabolized by CYP2C9 and, to a lesser extent, by CYP2C8.^{1 7 8}

Substrate of organic anionic transport polypeptide (OATP) 1B1 (OATP2) (see Extent under Pharmacokinetics);^{7 8 30} pharmacokinetic interactions observed with drugs that inhibit OATP1B1.^{1 7 9 30}

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Cyclosporine	Substantially increased peak plasma concentrations and AUC of pitavastatin1	Concomitant use contraindicated1
Digoxin	Slight decrease in peak plasma concentrations and increase in AUC of pitavastatin1 Slight decrease in peak plasma concentrations and AUC of digoxin1	Not considered clinically important29
Diltiazem	Slight increases in peak plasma concentration and AUC of pitavastatin; slight decreases in peak plasma concentration and AUC of diltiazem1
Enalapril	Decreased peak plasma concentrations and increased AUC of pitavastatin1 Increased peak plasma concentrations and AUC of enalapril1	Not considered clinically important29
Erythromycin	Substantially increased peak plasma concentrations and AUC of pitavastatin1	Do not exceed pitavastatin dosage of 1 mg once daily 1
Ezetimibe	Negligible decreases in peak plasma concentrations and AUC of pitavastatin1 Increased peak plasma concentrations and AUC of ezetimibe1	Not considered clinically important29
Fibric acid derivatives (e.g., fenofibrate, gemfibrozil)	Increased risk of myopathy or rhabdomyolysis1 Increased peak plasma concentration and AUC of pitavastatin; increases more pronounced when used concomitantly with gemfibrozil than with fenofibrate1	Gemfibrozil: Avoid concomitant use1 Other fibric acid derivatives (e.g., fenofibrate): Use concomitantly with caution1
Grapefruit juice	Decreased peak plasma concentrations and increased AUC of pitavastatin1	Not considered clinically important29
HIV protease inhibitors	Atazanavir: Increased peak plasma concentration and AUC of pitavastatin and atazanavir1 31 Ritonavir-boosted darunavir: Decreased peak plasma concentration and AUC of pitavastatin; increased peak plasma concentration and AUC of darunavir and ritonavir1 31 Lopinavir/ritonavir: Decreased peak plasma concentration and AUC of pitavastatin, lopinavir, and ritonavir1 31	Atazanavir: Not considered clinically important;29 dosage adjustment not necessary31 Ritonavir-boosted darunavir: Dosage adjustment not necessary31 Lopinavir/ritonavir: Dosage adjustment not necessary31
Itraconazole	Decreased peak plasma concentration and AUC of pitavastatin1	Not considered clinically important29
Niacin (antilipemic dosages29 [≥1 g daily])	Possible increased risk of myopathy1	Use concomitantly with caution; consider reducing pitavastatin dosage1
Rifampin	Substantially increased peak plasma concentration and AUC of pitavastatin; decreased peak plasma concentration and AUC of rifampin1	Do not exceed pitavastatin dosage of 2 mg once daily1
Warfarin	No clinically important pharmacokinetic interaction with R- and S-warfarin1 No clinically important effect on PT and INR in patients receiving long-term warfarin therapy1	Monitor PT and INR when pitavastatin is initiated in patients receiving warfarin1

Pitavastatin Calcium Pharmacokinetics

Absorption

Bioavailability

Absorbed from GI tract, principally from small intestine, with very small amounts absorbed from colon.¹

Absolute bioavailability of oral solution (not commercially available in the US) is 51%.¹

Peak plasma concentrations attained approximately 1 hour after administration of tablets²⁹ .¹

Peak plasma concentrations and AUC increase in an approximately dose-proportional manner for single pitavastatin dosages of 1–24 mg once daily.¹

Peak plasma concentrations and AUC reportedly not different following evening or morning administration; however, reductions in LDL-cholesterol concentrations achieved with 4-mg tablets slightly higher following evening administration compared with morning administration in healthy individuals.¹

Onset

Therapeutic response observed within one week; maximal response occurs within 2–4 weeks.²⁹

Food

High-fat meal (50% fat content) reduces peak plasma concentrations by 43% but does not substantially reduce extent of absorption (i.e., AUC).¹

Special Populations

Race: Peak plasma concentrations or AUC are 21 or 5% lower, respectively, in black individuals compared with white individuals; no substantial differences in peak plasma concentrations and AUC observed among Japanese and white individuals.¹

Gender: Peak plasma concentrations or AUC are 60 or 54% higher, respectively, in healthy women compared with healthy men; however, no difference in safety or efficacy observed in clinical trials.¹

Geriatric patients: Peak plasma concentrations or AUC are 10 or 30% higher, respectively, in geriatric individuals (≥65 years of age) compared with younger adults.¹ (See Geriatric Use under Cautions.)

Mild hepatic impairment (Child-Pugh class A): Peak plasma concentrations and AUC are 1.3- and 1.6-fold higher, respectively, than values in healthy individuals.¹

Moderate hepatic impairment (Child-Pugh class B): Peak plasma concentrations and AUC are 2.7- and 3.8-fold higher, respectively, than values in healthy individuals.¹

Patients with aminotransferase (AST, ALT) concentrations >1.5 times the ULN were excluded from phase 3 clinical studies.^{3 4 29}

Mild renal impairment: Effects on pitavastatin exposure are unknown.¹

Moderate renal impairment (GFR 30–59 mL/minute per 1.73 m²): Peak plasma concentrations and AUC are 60 and 102% higher, respectively, than values in healthy individuals.¹

Severe renal impairment (GFR 15–29 mL/minute per 1.73 m², not requiring hemodialysis): Peak plasma concentrations and AUC are 18 and 36% higher, respectively, than values in healthy individuals.¹

ESRD requiring hemodialysis: Peak plasma concentrations and AUC are 40 and 86% higher, respectively, than values in healthy individuals.¹

Distribution

Extent

Crosses placenta and is distributed into milk in rats.¹ (See Pregnancy and also Lactation under Cautions.)

Undergoes carrier-mediated uptake into hepatocytes, principally via OATP1B1 (OATP2) and, to a lesser extent, by OATP1B3 and OATP2B1;^{7 8 29 33} hepatic uptake is required for pharmacologic effects.⁷

Plasma Protein Binding

>99% (mainly albumin and alpha 1-acid glycoprotein).¹

Special Populations

Patients undergoing hemodialysis have a 33 or 36% increase in mean unbound fraction of pitavastatin compared with healthy individuals or patients with moderate renal impairment, respectively.¹

Elimination

Metabolism

Principally metabolized by uridine 5′-diphosphate (UDP) glucuronosyltransferase (i.e., UGT1A1, UGT1A3, UGT2B7) to an ester-type pitavastatin glucuronide conjugate, which is further metabolized to the inactive metabolite pitavastatin lactone.^{1 7 8}

Minimally metabolized by CYP2C9 and, to a lesser extent, by CYP2C8.^{1 7 8}

Elimination Route

Excreted in feces (79%) and in urine (15%) within 7 days following administration of oral solution (not commercially available in the US).^{1 29}

Unlikely to be removed by hemodialysis because of high (>99%) protein binding.¹

Half-life

Approximately 12 hours.¹

Special Populations

Mean elimination half-life is prolonged in patients with mild (10 hours) or moderate (15 hours) hepatic impairment compared with healthy individuals (8 hours).¹

Stability

Storage

Oral

Tablets

15–30°C. ¹ Protect from light.¹

Actions

• Inhibits HMG-CoA reductase, causing reduction in hepatic cholesterol biosynthesis; this leads to compensatory increase in expression of LDL receptors on hepatic cell surfaces and, subsequently, increased hepatic clearance of LDL-cholesterol from blood.^{1 7 8} Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, and triglyceride, and increases serum HDL-cholesterol concentrations in patients with primary hypercholesterolemia or mixed dyslipidemia.^{1 3 4 5 6}

• Statins may slow progression of and/or induce regression of atherosclerosis in coronary and/or carotid arteries,^{10 11 12 13 14 15 16 17 18 19 20 21 22 23 28} modulate BP in hypercholesterolemic patients with hypertension,^{24 25} and possess anti-inflammatory activity.^{26 27}

Advice to Patients

• Importance of adhering to nondrug therapies and measures, including dietary management, weight control, physical activity, and management of potentially contributory disease (e.g., diabetes mellitus).²

• Risk of myopathy and/or rhabdomyolysis.¹ Importance of promptly informing clinicians of any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.¹

• Risk of adverse hepatic effects.¹ Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).¹

• Risk of nonserious, reversible cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).^{1 200}

• Risk of increased glucose concentrations and development of type 2 diabetes;^{1 200} may need to monitor glucose concentrations following initiation of statin therapy.²⁰¹

• Importance of advising women to avoid pregnancy (i.e., using effective contraceptive methods) during therapy; if the patient becomes pregnant, importance of discontinuing pitavastatin and contacting a clinician.¹

• Importance of avoiding breast-feeding during therapy.¹ If the patient has a lipid disorder and is breast-feeding, importance of discontinuing pitavastatin and contacting a clinician.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pitavastatin Calcium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	1 mg (of pitavastatin)	Livalo	Kowa
		2 mg (of pitavastatin)	Livalo	Kowa
		4 mg (of pitavastatin)	Livalo	Kowa

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Livalo 1MG Tablets (LILLY): 30/$125.30 or 90/$356.45

Livalo 2MG Tablets (LILLY): 30/$124.99 or 90/$351.99

Livalo 4MG Tablets (LILLY): 30/$125.30 or 90/$356.45