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Pitavastatin

Class: HMG-CoA Reductase Inhibitors
- Statins
VA Class: CV350
Chemical Name: bis[(3R,5S,6E)-7-[2-Cyclopropyl-4-(p-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid] monocalcium
Molecular Formula: C50H46CaF2N2O8C50H46MgF2N2O8
CAS Number: 147526-32-7
Brands: Livalo, Zypitamag

Medically reviewed by Drugs.com on Dec 13, 2021. Written by ASHP.

Introduction

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

Uses for Pitavastatin

Available as pitavastatin calcium (e.g., Livalo) and pitavastatin magnesium (i.e., Zypitamag). FDA considers pitavastatin magnesium tablets to be a pharmaceutical alternative (as described in section 505[b][2] of the Federal Food, Drug, and Cosmetic Act) and not a pharmaceutical (generic) equivalent to pitavastatin calcium tablets, since both contain the same active moiety (pitavastatin) but have different salts. Clinical efficacy and safety expected to be similar between the 2 salt forms of the drug.

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. Also used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are on optimal statin therapy; however, no incremental benefit on cardiovascular morbidity and mortality beyond that provided by statin monotherapy.

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).

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

Reduction in Risk of Cardiovascular Events

Also may be used for reduction in the risk of atherosclerotic cardiovascular disease (ASCVD).

Extensive evidence demonstrates that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD; may be used for secondary prevention or primary prevention in high-risk patients.

AHA/ACC cholesterol management guideline states that lifestyle modification is the foundation of ASCVD risk reduction. Patients with established ASCVD or high risk of ASCVD should also be treated with a statin.

Because relative ASCVD risk reduction is correlated with degree of LDL-cholesterol lowering, use maximum tolerated intensity of a statin to achieve greatest benefit. High-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by ≥50%) is recommended; if high-intensity statin therapy not possible (e.g., because of a contraindication or intolerable adverse effect), may consider moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30–49%). AHA/ACC considers pitavastatin 1–4 mg daily to be a moderate-intensity statin.

The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) to statin therapy may be considered in certain high-risk patients who require further reduction in LDL-cholesterol concentrations, particularly if there is evidence from randomized controlled studies suggesting that the addition of the nonstatin drug further reduces ASCVD events.

When considering whether to initiate statin therapy for primary prevention, AHA/ACC recommends an individualized approach and shared decision making between patient and clinician. According to the guidelines, statin therapy may be considered in certain high-risk groups such as adults 20–75 years of age with LDL cholesterol ≥190 mg/dL, adults 40–75 years of age with diabetes mellitus, adults 40–75 years of age without diabetes mellitus but with LDL-cholesterol levels ≥70 mg/dL and an estimated 10-year ASCVD risk ≥7.5%, and adults 40–75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70–189 mg/dL who have a 10-year ASCVD risk ≥7.5%.

Pitavastatin Dosage and Administration

General

Patient Monitoring

    Antilipemic Therapy
  • Manufacturers recommend obtaining lipoprotein concentrations within 4 weeks following initiation and/or titration of pitavastatin and adjusting dosage accordingly. AHA/ACC cholesterol management guideline recommends obtaining lipoprotein concentrations within 4–12 weeks following initiation of statin therapy and after dosage changes (to assess response and adherence); monitoring should continue every 3–12 months thereafter as clinically indicated.

  • Periodically reinforce adherence to lifestyle modifications during statin therapy. Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of ASCVD.

Administration

Oral Administration

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

Dosage

Available as pitavastatin calcium (e.g., Livalo) and pitavastatin magnesium (i.e., Zypitamag); dosages expressed in terms of pitavastatin. Commercially available tablets of Livalo and Zypitamag are considered bioequivalent.

Dosage modifications may be necessary when used concomitantly with certain drugs (see Specific Drugs and Foods under Interactions).

Adults

Reduction in Risk of Cardiovascular Events†
Oral

Use maximally tolerated statin intensity to achieve optimal ASCVD risk reduction. High-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by ≥50%) is preferred; if high-intensity statin therapy not possible (e.g., because of a contraindication or intolerable adverse effect), may consider a moderate-intensity statin (defined as reducing LDL-cholesterol concentrations by 30–49%).

The AHA/ACC guideline panel considers pitavastatin 1–4 mg daily to be a moderate-intensity statin.

Dyslipidemias
Primary Hypercholesterolemia or Mixed Dyslipidemia
Oral

Initially, 2 mg once daily. Usual maintenance dosage is 1–4 mg once daily.

Prescribing Limits

Adults

Dyslipidemias
Primary Hypercholesterolemia or Mixed Dyslipidemia
Oral

Maximum 4 mg once daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time. (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. Maximum 2 mg once daily.

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

Geriatric Patients

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

Cautions for Pitavastatin

Contraindications

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

  • Concomitant use with cyclosporine.

  • Lactation.

  • Known hypersensitivity to pitavastatin or any ingredient in the formulation.

Warnings/Precautions

Musculoskeletal Effects

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

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins. Characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, necrotizing myopathy without substantial inflammation, and improvement following therapy with immunosuppressive agents.

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). (See Interactions.)

AHA/ACC recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.

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

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.)

Hepatic Effects

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

Fatal and nonfatal hepatic failure reported rarely.

Perform liver function tests prior to initiation of therapy and as clinically indicated (e.g., presence of manifestations suggestive of liver damage). Serious statin-related liver injury with statins is rare and unpredictable, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. AHA/ACC cholesterol management guideline states that it is reasonable to obtain liver function tests in patients with symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of skin or sclera); however, routine monitoring not recommended.

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt pitavastatin therapy. If an alternate etiology is not found, do not restart pitavastatin. (See Hepatic Impairment under Cautions.)

Use with caution in patients who consume substantial amounts of alcohol. Contraindicated in patients with active liver disease.

Endocrine Effects

Increases in HbA1c and fasting serum glucose concentrations reported. Possible increased risk of developing diabetes. May need to monitor glucose concentrations following initiation of statin therapy.

AHA/ACC cholesterol management guideline states that in patients with increased risk of diabetes mellitus or new-onset diabetes mellitus, statin therapy and lifestyle modifications should be continued to reduce risk of ASCVD.

Cognitive Impairment

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

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

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

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

Specific Populations

Pregnancy

All statins were previously contraindicated in pregnant women because fetal risk was thought to outweigh any possible benefit. However, the totality of evidence to date indicates limited potential for statins to cause malformations and other adverse embryofetal effects; FDA has therefore requested removal of the contraindication. Most pregnant patients should still discontinue statins because of the possibility of fetal harm; however, some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) may benefit from continued therapy. Consider patient's individual risks and benefits.

Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician; clinician should advise patient on the appropriate course of action.

Increased risk of miscarriage reported in pregnant women exposed to statins; however, not clear whether drug-related or due to other confounding factors.

Lactation

Not known whether distributed into human milk; however, another statin has been shown to distribute into human milk. Use of pitavastatin is contraindicated. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

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

Patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy; consider expected benefits versus adverse effects before initiating statin therapy in this population.

Hepatic Impairment

Contraindicated in patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.

Renal Impairment

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

Common Adverse Effects

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

Interactions for Pitavastatin

Minimally metabolized by CYP2C9 and, to a lesser extent, by CYP2C8.

Substrate of organic anionic transport polypeptide (OATP) 1B1 (OATP2) (see Extent under Pharmacokinetics); pharmacokinetic interactions observed with drugs that inhibit OATP1B1.

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Colchicine

Myopathy, including rhabdomyolysis, reported

Use concomitantly with caution

Digoxin

Slight decrease in peak plasma concentrations and increase in AUC of pitavastatin

Slight decrease in peak plasma concentrations and AUC of digoxin

Not considered clinically important

Diltiazem

Slight increases in peak plasma concentration and AUC of pitavastatin; slight decreases in peak plasma concentration and AUC of diltiazem

Enalapril

Decreased peak plasma concentrations and increased AUC of pitavastatin

Increased peak plasma concentrations and AUC of enalapril

Not considered clinically important

Erythromycin

Substantially increased peak plasma concentrations and AUC of pitavastatin

Do not exceed pitavastatin dosage of 1 mg once daily

Ezetimibe

Negligible decreases in peak plasma concentrations and AUC of pitavastatin

Increased peak plasma concentrations and AUC of ezetimibe

Not considered clinically important

Fibric acid derivatives (e.g., fenofibrate, gemfibrozil)

Increased risk of myopathy or rhabdomyolysis

Increased peak plasma concentration and AUC of pitavastatin; increases more pronounced when used concomitantly with gemfibrozil than with fenofibrate

Gemfibrozil: Avoid concomitant use

Other fibric acid derivatives (e.g., fenofibrate): Use concomitantly with caution and only if benefits outweigh risks; consider using only low- or moderate-intensity statin therapy during concomitant therapy

Grapefruit juice

Decreased peak plasma concentrations and increased AUC of pitavastatin

Not considered clinically important

HIV protease inhibitors

Atazanavir: Increased peak plasma concentration and AUC of pitavastatin and atazanavir

Ritonavir-boosted darunavir: Decreased peak plasma concentration and AUC of pitavastatin; increased peak plasma concentration and AUC of darunavir and ritonavir

Lopinavir/ritonavir: Decreased peak plasma concentration and AUC of pitavastatin, lopinavir, and ritonavir

Atazanavir: Not considered clinically important; dosage adjustment not necessary

Ritonavir-boosted darunavir: Dosage adjustment not necessary

Lopinavir/ritonavir: Dosage adjustment not necessary

Immunosuppressive agents (i.e., cyclosporine, everolimus, sirolimus, tacrolimus)

Cyclosporine: Substantially increased peak plasma concentrations and AUC of pitavastatin

Everolimus, sirolimus, tacrolimus: Data more limited, but interaction potential expected to be similar to cyclosporine because of similar metabolism

Cyclosporine: Concomitant use contraindicated

Everolimus, sirolimus, tacrolimus: Some experts recommend avoiding concomitant use

Itraconazole

Decreased peak plasma concentration and AUC of pitavastatin

Not considered clinically important

Niacin (antilipemic dosages [≥1 g daily])

Possible increased risk of myopathy

Increased risk of severe adverse effects (disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, bleeding) with concomitant use of niacin (1.5–2 g daily) and simvastatin (40–80 mg daily, with or without ezetimibe)

Use concomitantly with caution; consider reducing pitavastatin dosage

Rifampin

Substantially increased peak plasma concentration and AUC of pitavastatin; decreased peak plasma concentration and AUC of rifampin

Do not exceed pitavastatin dosage of 2 mg once daily

Warfarin

No clinically important pharmacokinetic interaction with R- and S-warfarin

No clinically important effect on PT and INR in patients receiving long-term warfarin therapy

Monitor PT and INR when pitavastatin is initiated and when dosage is changed in patients receiving warfarin

Pitavastatin Pharmacokinetics

Absorption

Bioavailability

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

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

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

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

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.

Pitavastatin calcium tablets (Livalo) are bioequivalent to pitavastatin magnesium tablets (Zypitamag) under fasting conditions.

Onset

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

Food

High-fat meal (50% fat content) reduces peak plasma concentrations of pitavastatin by 43% when administered as the calcium salt; high-fat meal (50% fat content) reduced peak plasma concentrations of pitavastatin by 39% when administered as the magnesium salt. Extent of absorption (i.e., AUC) not substantially reduced when either formulation was administered with a high-fat meal.

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.

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.

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

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.

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

Mild renal impairment: Effects on pitavastatin exposure are unknown.

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.

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.

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

Distribution

Extent

Crosses placenta in rats. (See Pregnancy.)

Not known whether pitavastatin is distributed into human milk.

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

Plasma Protein Binding

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

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.

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.

Minimally metabolized by CYP2C9 and, to a lesser extent, by CYP2C8.

Elimination Route

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

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

Half-life

Approximately 12 hours.

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).

Stability

Storage

Oral

Tablets

Pitavastatin calcium: 15–30°C. Protect from light.

Pitavastatin magnesium: 20–25°C. Protect from moisture and light.

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. 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.

  • Statins may slow progression of and/or induce regression of atherosclerosis in coronary and/or carotid arteries, modulate BP in hypercholesterolemic patients with hypertension, and possess anti-inflammatory activity.

Advice to Patients

  • Importance of adhering to nondrug therapies and measures, including adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.

  • Risk of myopathy and/or rhabdomyolysis; risk is increased with higher dosages or when used concomitantly with certain drugs. Importance of promptly informing clinicians of any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if manifestations persist after discontinuance of therapy.

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

  • Risk of nonserious, reversible cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).

  • Risk of increased glucose concentrations and development of type 2 diabetes; may need to monitor glucose concentrations following initiation of statin therapy.

  • Importance of advising women to notify their clinician if they become pregnant during therapy.

  • Importance of avoiding breast-feeding during therapy.

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

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Pitavastatin Calcium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

1 mg (of pitavastatin)*

Livalo

Kowa

Pitavastatin Calcium Tablets

2 mg (of pitavastatin)*

Livalo

Kowa

Pitavastatin Calcium Tablets

4 mg (of pitavastatin)*

Livalo

Kowa

Pitavastatin Calcium Tablets

Pitavastatin Magnesium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

1 mg (of pitavastatin)

Zypitamag

Medicure

2 mg (of pitavastatin)

Zypitamag

Medicure

4 mg (of pitavastatin)

Zypitamag

Medicure

AHFS DI Essentials™. © Copyright 2022, Selected Revisions December 13, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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