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. Last updated on Nov 23, 2020.

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Introduction

Antilipemic agent; hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin).^{1 36}

Uses for Pitavastatin

Available as pitavastatin calcium (e.g., Livalo) and pitavastatin magnesium (i.e., Zypitamag).^{1 36} 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.^{1 36 38 39 40 41} Clinical efficacy and safety expected to be similar between the 2 salt forms of the drug.^{1 36 38 41 42}

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 36} 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.^{35 353}

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 36} Effect on cardiovascular morbidity and mortality not established.^{1 36}

Prevention of Cardiovascular Events

ACC/AHA cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults; extensive evidence demonstrates that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients).^{336 337 338 350} Relative reduction in ASCVD risk is correlated with degree of LDL-cholesterol lowering; therefore, use maximum tolerated statin intensity to achieve optimum ASCVD benefits.³⁵⁰ According to ACC/AHA, pitavastatin may be used for primary† or secondary prevention† in adults when moderate-intensity statin therapy is indicated.³⁵⁰ (See Prevention of Cardiovascular Events under Dosage and Administration.)

Current recommendations from ACC/AHA regarding prevention of ASCVD and lifestyle modifications to reduce atherosclerotic risk are available at [Web] or [Web].^{350 352}

Pitavastatin 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 36}

Monitoring during Antilipemic Therapy

• Manufacturers recommend obtaining lipoprotein concentrations within 4 weeks following initiation and/or titration of pitavastatin and adjusting dosage accordingly.^{1 36} ACC/AHA cholesterol management guideline recommends obtaining lipoprotein concentrations within 4–12 weeks following initiation of statin therapy (to assess response and adherence) and monitoring every 3–12 months thereafter as clinically indicated.³⁵⁰

• Periodically reinforce adherence to lifestyle modifications during statin therapy.³⁵⁰

Administration

Oral Administration

Administer orally once daily at any time of day, without regard to food.^{1 36}

Dosage

Available as pitavastatin calcium (e.g., Livalo) and pitavastatin magnesium (i.e., Zypitamag); dosages expressed in terms of pitavastatin.^{1 36} Commercially available tablets of Livalo and Zypitamag are considered bioequivalent.^{37 42}

Adults

Prevention of Cardiovascular Events†

Select appropriate statin intensity to achieve optimal ASCVD risk reduction.³⁵⁰ Giving maximally tolerated statin intensity is preferred over giving lower statin dosages in combination with nonstatin drugs, a strategy not yet shown to reduce ASCVD risk.³⁵⁰

Although dosages of 1–4 mg once daily are FDA-labeled dosages, these dosages were not evaluated in randomized controlled studies reviewed by the ACC/AHA expert panel.³⁵⁰

Primary Prevention† in Patients with LDL-cholesterol Concentrations ≥190 mg/dL (≥21 years of age)

Oral

ACC/AHA cholesterol management guideline recommends initiating high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated.³⁵⁰

Primary Prevention† in Patients with Type 1 or 2 Diabetes Mellitus (40–75 years of age)

Oral

ACC/AHA cholesterol management guideline recommends moderate-intensity statin therapy (e.g., pitavastatin 2–4 mg once daily).³⁵⁰

If estimated 10-year ASCVD risk ≥7.5%, consider high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated.³⁵⁰

In patients <40 or >75 years of age, consider potential benefits, adverse effects, drug interactions, and patient preferences when deciding to initiate, continue, or intensify statin therapy.³⁵⁰

Primary Prevention† in Patients with LDL-cholesterol Concentrations 70–189 mg/dL and Elevated ASCVD Risk (40–75 years of age)

Oral

Estimated 10-year ASCVD risk ≥7.5%: ACC/AHA cholesterol management guideline recommends moderate- (e.g., pitavastatin 2–4 mg once daily) to high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin).³⁵⁰

Estimated 10-year ASCVD risk of 5 to <7.5%: ACC/AHA cholesterol management guideline states may consider moderate-intensity statin therapy.³⁵⁰

Consider potential benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.³⁵⁰

Secondary Prevention† in Patients with Clinical ASCVD (i.e., acute coronary syndromes; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) (21–75 years of age)

Oral

ACC/AHA cholesterol management guideline recommends high-intensity statin therapy (i.e., with atorvastatin or rosuvastatin) unless contraindicated.³⁵⁰

In patients at increased risk for developing statin-associated adverse effects or in whom high-intensity statin therapy is inappropriate or contraindicated, consider moderate-intensity statin therapy (e.g., pitavastatin 2–4 mg once daily) if tolerated.³⁵⁰

Patients >75 years of age: Individualize therapy based on potential benefits, adverse effects, drug interactions, and patient preferences; may consider moderate-intensity statin therapy if tolerated.³⁵⁰

Dyslipidemias

Primary Hypercholesterolemia or Mixed Dyslipidemia

Oral

Initially, 2 mg once daily.^{1 36} Usual maintenance dosage is 1–4 mg once daily.^{1 36}

Dosage Modification

Oral

ACC/AHA cholesterol management guideline states may consider decreasing statin dosage when LDL-cholesterol concentrations are <40 mg/dL on 2 consecutive measurements; however, no data to suggest that LDL-cholesterol concentrations <40 mg/dL increase risk of adverse effects.³⁵⁰

Prescribing Limits

Adults

Dyslipidemias

Primary Hypercholesterolemia or Mixed Dyslipidemia

Oral

Maximum 4 mg once daily.^{1 36}

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^{1 36} (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 36} Maximum 2 mg once daily.^{1 36}

End-stage renal disease (ESRD) requiring hemodialysis: Initially, 1 mg once daily.^{1 36} Maximum 2 mg once daily.^{1 36}

Geriatric Patients

No specific dosage recommendations at this time.^{1 36} (See Geriatric Use under Cautions.)

Cautions for Pitavastatin

Contraindications

• Active liver disease, including unexplained, persistent elevations of serum aminotransferase concentrations.^{1 36}

• Concomitant use with cyclosporine.^{1 36} (See Specific Drugs and Foods under Interactions.)

• Pregnancy.^{1 36} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Lactation.^{1 36} (See Lactation under Cautions.)

• Known hypersensitivity to pitavastatin or any ingredient in the formulation.^{1 36} (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Suppression of cholesterol biosynthesis by pitavastatin could cause fetal harm.^{1 36} Congenital anomalies following intrauterine exposure to statins reported rarely.¹

Advise women of childbearing potential to use effective contraceptive methods during pitavastatin therapy.^{1 36} If pregnancy is known or suspected, discontinue therapy.^{1 36}

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

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported rarely in patients receiving statins.¹ 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.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 36} (See Interactions.)

ACC/AHA cholesterol management guideline does not recommend routine monitoring of CK concentrations in adults; however, may obtain CK concentrations before initiating therapy in adults at increased risk of developing adverse musculoskeletal effects (e.g., patients with personal or family history of statin intolerance or muscle disease, patients receiving concomitant therapy with myotoxic drugs).³⁵⁰ During statin therapy, may measure CK concentrations in adults with muscle symptoms (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue).³⁵⁰

Discontinue if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.^{1 36}

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).^{1 36} (See Advice to Patients.)

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 damage).^{1 36 201} Although one 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 ACC/AHA cholesterol management guideline recommends obtaining liver function tests in adults with symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of skin or sclera).³⁵⁰

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt pitavastatin therapy.^{1 36} If an alternate etiology is not found, do not restart pitavastatin.^{1 36} (See Hepatic Impairment under Cautions.)

Use with caution in patients who consume substantial amounts of alcohol.^{1 36} Contraindicated in patients with active liver disease.^{1 36} (See Contraindications under Cautions.)

Endocrine 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

ACC/AHA cholesterol management guideline recommends evaluating patients for new-onset diabetes mellitus according to current diabetes screening guidelines.³⁵⁰

If diabetes mellitus develops during statin therapy, encourage patients to adhere to a heart-healthy diet, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of ASCVD.³⁵⁰

Sensitivity Reactions

Hypersensitivity reactions, including rash, pruritus, and urticaria, reported.^{1 36}

Cognitive Impairment

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) reported rarely.^{1 36}

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 36 200} 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

If patients present with confusion or memory impairment, ACC/AHA cholesterol management guideline recommends evaluating patient for statin as well as nonstatin causes (e.g., other drugs, systemic or neuropsychiatric causes).³⁵⁰

Specific Populations

Pregnancy

Use contraindicated.^{1 36} Safety not established in pregnant women; no known benefit of therapy during pregnancy.^{1 36} (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Discontinue drug immediately if pregnancy is known or suspected.^{1 36} Women of childbearing potential should use effective contraceptive methods while receiving the drug.^{1 36} (See Advice to Patients.)

Lactation

Not known whether distributed into human milk; however, another statin has been shown to distribute into human milk.^{1 36} Use of pitavastatin is contraindicated.^{1 36}

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.^{1 29 36}

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.^{1 36} In patients >75 years of age, consider benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.³⁵⁰

Hepatic Impairment

Contraindicated in patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.^{1 36} (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 36} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

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

Interactions for Pitavastatin

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

Pitavastatin 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 tablets.^{1 29}

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

Pitavastatin calcium tablets (Livalo) are bioequivalent to pitavastatin magnesium tablets (Zypitamag) under fasting conditions.^{37 42}

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 of pitavastatin by 43% when administered as the calcium salt;¹ high-fat meal (50% fat content) reduced peak plasma concentrations of pitavastatin by 39% when administered as the magnesium salt.^{36 37} Extent of absorption (i.e., AUC) not substantially reduced when either formulation was administered with a high-fat meal.^{1 36 37}

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 in rats.¹ (See Pregnancy.)

Not known whether pitavastatin is distributed into human milk.^{1 36}

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 36}

Minimally metabolized by CYP2C9 and, to a lesser extent, by CYP2C8.^{1 7 8 36}

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

Pitavastatin calcium: 15–30°C.¹ Protect from light.¹

Pitavastatin magnesium: 20–25°C.³⁶ Protect from moisture and light.³⁶

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 36} 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 36}

• 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 adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.^{2 350}

• Risk of myopathy and/or rhabdomyolysis; risk is increased with higher dosages or when used concomitantly with certain drugs.^{1 36} 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.^{1 36}

• Risk of adverse hepatic effects.^{1 36} Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).^{1 36}

• Risk of nonserious, reversible cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).^{1 36 200}

• Risk of increased glucose concentrations and development of type 2 diabetes;^{1 36 200} may need to monitor glucose concentrations following initiation of statin therapy.²⁰¹

• Importance of advising women of childbearing potential to avoid pregnancy (i.e., by using effective and appropriate contraceptive methods) during therapy; if pregnancy is known or suspected, importance of discontinuing pitavastatin and contacting a clinician.^{1 36}

• Importance of avoiding breast-feeding during therapy.^{1 36}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{1 36}

• Importance of informing patients of other important precautionary information.^{1 36} (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

Frequently asked questions

• What are the side effects of statins?
• How is Livalo (pitavastatin) different from other statins?
• When is the best time of day to take Livalo (pitavastatin)?
• Can you drink alcohol while taking Livalo (pitavastatin)?

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