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Introduction ⬇

AHFS Class:

Generic Name(s):

Pitavastatin calcium and pitavastatin magnesium, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (i.e., statins), are antilipemic agents.1,36

Uses ⬆ ⬇

[Section Outline]

Pitavastatin is commercially available in the US as pitavastatin calcium (e.g., Livalo®and generic equivalents) and as 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 studies establishing efficacy and safety of pitavastatin for the treatment of dyslipidemias have been conducted with the calcium salt form of the drug.1,42 Because pitavastatin calcium and pitavastatin magnesium contain the same active moiety (pitavastatin), clinical efficacy is expected to be similar between the 2 different salts.1,36,38,41,42

Dyslipidemias !!navigator!!

Pitavastatin is used as an adjunct to diet to decrease low-density lipoprotein (LDL)-cholesterol in adults with primary hyperlipidemia and in pediatric patients 8 years of age or older with heterozygous familial hypercholesterolemia.1,36

Primary Hyperlipidemia in Adults

Pitavastatin is used as an adjunct to diet to decrease LDL-cholesterol in the management of adults with primary hyperlipidemia.1,36 Safety and efficacy of pitavastatin for this use were established in placebo-controlled and comparative studies in patients with primary hyperlipidemia or mixed dyslipidemia.1,3,4,5,6

In these studies, reductions in total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations achieved with usual dosages of pitavastatin substantially exceeded those with placebo.43 In 2 randomized, double-blind, placebo-controlled, phase 2, dose-ranging studies in 399 patients 21-75 years of age with primary hyperlipidemia, mean reductions of 19-33% in total cholesterol, 27-45% in LDL-cholesterol, 23-37% in apo B, and 14-25% in triglyceride concentrations were reported in patients receiving pitavastatin 1-4 mg daily for 12 weeks.43 Modest increases in HDL-cholesterol concentrations (8-10%) also were observed in these patients.1,43

Data from comparative studies indicate that 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 In a double-blind, active-controlled, noninferiority, phase 3 study in which 817 patients 18-75 years of age with primary hyperlipidemia or mixed dyslipidemia were randomized to receive either pitavastatin or atorvastatin for 12 weeks, reductions in LDL-cholesterol concentrations achieved with pitavastatin 2 or 4 mg daily (38 or 45%, respectively) were noninferior to those achieved with atorvastatin 10 mg or 20 mg daily (38 or 44%, respectively).1,3 In another double-blind, active-controlled, noninferiority, phase 3 study in which 843 patients 18-75 years of age with primary hyperlipidemia or mixed dyslipidemia were randomized to receive either pitavastatin or simvastatin for 12 weeks, reductions in LDL-cholesterol concentrations achieved with pitavastatin 2 or 4 mg daily (39 or 44%, respectively) were noninferior to those achieved with simvastatin 20 or 40 mg daily (35 or 43%, respectively).1,4,9 In a third double-blind, active-controlled, noninferiority, phase 3 study in which 942 geriatric patients (65 years of age or older) with primary hyperlipidemia or mixed dyslipidemia were randomized to receive either pitavastatin or pravastatin for 12 weeks, reductions in LDL-cholesterol concentrations achieved with pitavastatin 1, 2, or 4 mg daily (31, 39, or 44%, respectively) were greater than those achieved with pravastatin 10, 20, or 40 mg daily (22, 29, or 34%, respectively).1,5

In patients who have risk factors for coronary heart disease (CHD), reductions in LDL-cholesterol concentrations achieved with the maximum dosage (4 mg daily) of pitavastatin are similar to or less than those achieved with low to medium dosages of certain other statins (i.e., atorvastatin, simvastatin).1 In a double-blind, active-controlled, noninferiority, phase 3 study in which 351 patients with primary hyperlipidemia or mixed dyslipidemia and 2 or more risk factors for CHD were randomized to receive either pitavastatin or simvastatin for 12 weeks, reductions in LDL-cholesterol concentrations achieved with pitavastatin 4 mg daily were noninferior to those achieved with simvastatin 40 mg daily (44 versus 44%).1 In another double-blind, active-controlled, noninferiority, phase 3 study in which 410 patients with mixed dyslipidemia and type 2 diabetes mellitus were randomized to receive either pitavastatin or atorvastatin for 12 weeks, reductions in LDL-cholesterol concentrations achieved with pitavastatin 4 mg daily (41%) were not noninferior to those achieved with atorvastatin 20 mg daily (43%).1

Antilipemic effects of pitavastatin appear to be sustained during long-term (i.e., up to 2 years) therapy.5,6 In an open-label extension study in 1353 patients with primary hyperlipidemia or mixed dyslipidemia who had previously received pitavastatin, atorvastatin, or simvastatin for 12 weeks in double-blind phase 3 studies, treatment with pitavastatin 4 mg daily for up to 52 weeks resulted in reductions of approximately 30% in total cholesterol, 43% in LDL-cholesterol, 36% in apo B, and 17% in triglyceride concentrations, and increases of approximately 14% in HDL-cholesterol concentrations; with the exception of substantially greater increases in HDL-cholesterol concentrations, these antilipemic effects were similar to those observed at the end of the 12-week. double-blind, phase 3 studies.6 In another extension study in 545 geriatric patients (65 years of age or older) who had previously received pitavastatin or pravastatin for 12 weeks in a double-blind, phase 3 study, treatment with pitavastatin 2 mg daily (titrated to 4 mg daily after 8 weeks as needed to achieve target LDL-cholesterol goal) for 60 weeks resulted in reductions of approximately 43 or 20% in LDL-cholesterol or triglyceride concentrations (pooled data), respectively, and an increase of approximately 10% in HDL-cholesterol concentrations (pooled data), compared with baseline concentrations (i.e., prior to initiation of the 12-week, double-blind, phase 3 study); at week 60, approximately 94% of patients receiving pitavastatin achieved their LDL-cholesterol goals based on NCEP ATP III.45 In an uncontrolled, observational postmarketing surveillance study, LDL-cholesterol concentrations were reduced by approximately 29% and HDL-cholesterol concentrations increased by approximately 6% at 2 years following initiation of pitavastatin therapy.46 At year 5 of this extension study, LDL-cholesterol was maintained for the duration of treatment and HDL-cholesterol continued to rise.46

Pitavastatin alone or in combination with ezetimibe improves the atherogenic lipid profile in patients with hyperlipidemia.47,48 In an 8-week, randomized, double-blind, active-controlled, phase 3 study of 283 patients with primary hyperlipidemia who were treated with pitavastatin (2 or 4 mg daily) alone or in combination with ezetimibe 10 mg daily, LDL-cholesterol was reduced by approximately 37 and 52% and total cholesterol was reduced by approximately 26 and 36% from baseline, respectively; triglyceride and HDL-cholesterol levels did not change significantly.47 Overall rates of achieving the LDL-cholesterol target, based on NCEP ATP III guidelines, were approximately 94 and 69% in the pooled pitavastatin/ezetimibe and pooled pitavastatin groups, respectively.48 In a 12-week randomized, double-blind, active-controlled, phase 3 trial, 288 patients with hyperlipidemia were treated with pitavastatin (2 or 4 mg daily) alone or in fixed combination with ezetimibe 10 mg daily.47 LDL-cholesterol was reduced by approximately 40, 45, 51, and 58% in patients receiving pitavastatin 2 mg, pitavastatin 4 mg, pitavastatin 2 mg/ezetimibe 10 mg and pitavastatin 4 mg/ezetimibe 10 mg, respectively; the fixed combination reductions were superior to the corresponding dose of pitavastatin monotherapy.47 Significant reductions in total cholesterol (approximately 27, 31, 35, 40%, respectively) and non-HDL-cholesterol (approximately 37, 42, 48, 55%, respectively) were also observed.47

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

Pitavastatin is used as an adjunct to diet to reduce LDL-cholesterol in pediatric patients 8 years of age and older with heterozygous familial hypercholesterolemia (HeFH).1 Pediatric use of pitavastatin is FDA-labeled only for the Livalo® preparation; Zypitamag® is currently not labeled by FDA for this indication.36

Efficacy and safety of pitavastatin in pediatric patients with HeFH were evaluated in a double-blind, placebo-controlled, 12-week study of 82 patients 8-16 years of age with genetically confirmed HeFH, fasting LDL-cholesterol ≥190 mg/dL or LDL-cholesterol ≥160 mg/dL with an additional cardiovascular risk factor (i.e., male gender, family history of premature cardiovascular disease, presence of low HDL-cholesterol [<45 mg/d] or high triglyceride levels [>150 mg/dL], presence of high lipoprotein (a) [>75 nmol/L], presence of type 2 diabetes mellitus, or presence of hypertension).1 Patients were randomized to pitavastatin (1, 2, or 4 mg) or placebo daily.1 Mean baseline LDL-cholesterol was 235 mg/dL; 39% of patients were Tanner stage 1 at baseline.1 LDL-cholesterol, total cholesterol, non-HDL-cholesterol, and apo-B were reduced by 21-38, 16-30, 21-36, and 20-28%, respectively at 12 weeks; such reductions, compared to placebo, were significant and dose dependent.1 The manufacturer states that safety and effectiveness of pitavastatin for this indication are also supported by a 52-week, open-label trial in 85 pediatric patients with HeFH.1

Clinical Perspective

Elevated serum cholesterol, especially the LDL-cholesterol fraction, is a major cause of atherosclerotic cardiovascular disease (ASCVD); other major risk factors include cigarette smoking, hypertension, diabetes, age, HeFH, chronic kidney disease (eGFR 15-59 mL/minute per 1.73 m2), history of heart failure, and other lipoprotein abnormalities.400,403 The goal of antilipemic therapy in patients with hyperlipidemia is to reduce the risk of ASCVD.400 Pitavastatin 1-4 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400

The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, statin therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of ASCVD.400,401,402

When considering whether to initiate statin therapy for dyslipidemia in the setting of primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥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 of 7.5% or higher.400,401

There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for such patients.336,337,338,400,401,402,403 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400,401,402

Combination Antilipemic Therapy

An ACC expert committee update on nonstatin drug therapies recommends that adults without ASCVD with baseline LDL-cholesterol concentrations >190 mg/dL not due to secondary causes may be considered for ezetimibe and/or a PCSK9 monoclonal antibody (mAb) if they have not met certain thresholds of LDL-cholesterol reduction on maximally tolerated statin therapy for primary prevention (e.g., at least 50% reduction in LDL-cholesterol with an LDL-cholesterol <100 mg/dL or a non-HDL-cholesterol concentration <130 mg/dL).403 Individuals with LDL-cholesterol concentrations >190 mg/dL are more likely to have genetic disorders associated with hypercholesterolemia, such as HeFH or homozygous familial hypercholesterolemia.403 Current treatments for patients with HeFH include lifestyle modifications (e.g., low-fat diet, maintenance of a healthy body weight, smoking cessation), first-line treatment with statins, and, if necessary, combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran).403

Pediatric Patients

In addition to early identification of children with familial hypercholesterolemia (FH), dietary (e.g., caloric restriction, Mediterranean-style diet) and lifestyle modification (e.g., physical activity) are prioritized for the management of hypercholesterolemia in children and adolescents.400,404 Evidence from randomized controlled trials coupled with the increased risk of cardiovascular disease in untreated severe hypercholesterolemia, support the use of statins in children and adolescents ≥10 years of age who have FH.400

In children and adolescents ≥10 years of age with an LDL-cholesterol level persistently ≥190 mg/dL or ≥160 mg/dL with a clinical presentation consistent with FH and who do not respond adequately with 3-6 months of lifestyle therapy, experts state it is reasonable to initiate statin therapy.400 Experts state that statins may be considered as early as 8 years of age in the presence of concerning family history, extremely elevated LDL-cholesterol level, or elevated lipoprotein (a) and in the context of informed shared decision-making and counseling with the patient and family.400,404 Treatment intensity should be based on the severity of the hypercholesterolemia and should incorporate patient/family preference; some experts recommend initiation at the lowest recommended dose and up-titration according to LDL-cholesterol lowering response and tolerability.400,404 Some experts recommend a target LDL-cholesterol level <130 mg/dL or ≥50% reduction from pre-treatment levels, particularly in those with high-risk conditions or other major risk factors; combination therapy with other lipid-lowering medications (e.g., bile acid sequestrants, ezetimibe) may be required.404

Reduction in Risk of Cardiovascular Events !!navigator!!

Pitavastatin also has been used for reduction in the risk of atherosclerotic cardiovascular disease (ASCVD)† in patients with established ASCVD or in patients at high risk of ASCVD.49,50,400

Chronic Kidney Disease

The potential benefits of pitavastatin in patients with chronic kidney disease receving hemodialysis, a population at high risk of cardiovascular disease, were evaluated in the DIALYSIS trial, a randomized, open-label study in 848 patients undergoing hemodialysis.49 Patients were treated with pitavastatin 1-4 mg daily or dietary therapy (control group); mean length of followup was 36.9 months (maximum 67.4 months).49 After adjusting for confounding factors, therapy with pitavastatin reduced the primary endpoint of all-cause death and new nonfatal MI and the composite endpoint of cardiovascular death, cardiovascular event-free survival (i.e., nonfatal MI, serious arrhythmia, coronary revascularization such as percutaneous coronary intervention and coronary artery bypass grafting), admission for unstable angina and congestive heart failure, nonfatal cerebrovascular events, and bone fracture.49

HIV Infection

The potential benefits of pitavastatin in patients with human immunodeficiency virus (HIV) infection, a population at higher risk of ASCVD, including MI and stroke, were evaluated in the REPRIEVE trial.50 REPRIEVE was a randomized, placebo-controlled, phase 3 trial in 7769 patients 40-75 years of age with HIV infection and a low-to-moderate risk of ASCVD on stable antiretroviral therapy; patients were treated with pitavastatin calcium 4 mg or placebo daily.50 The median age of patients was 50 years; 68.9% were male, and approximately 41, 35, and 15% were white, Black, and Asian, respectively.50 The median screening LDL-cholesterol was 108 mg/dL and median CD4+ count was 621 cells/mm3; among those with quantifiable viremia, the median viral load was 62 copies/mL.50 The primary outcome was major adverse cardiovascular events, defined as a composite of cardiovascular death, MI, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization of a coronary, carotid, or peripheral artery, or death from an undetermined cause.50 The primary outcome was reduced by 35% with pitavastatin.50 The secondary outcome, first major adverse cardiovascular event or death from any cause, was reduced by 21%.50 The trial was stopped early for efficacy with no unexpected safety concerns after a median follow-up of 5.1 years.50

Clinical Perspective

The 2018 AHA/ACC cholesterol management guideline emphasizes lifestyle modification as the foundation of ASCVD risk reduction.400 If pharmacologic therapy is needed, statin therapy is recommended.400 Statins are considered the first-line drugs of choice for reducing LDL-cholesterol, the lipoprotein fraction found to be a major cause of ASCVD.400 There is extensive evidence demonstrating that statins can substantially reduce LDL-cholesterol concentrations and associated risk of ASCVD when used for secondary or primary prevention.336,337,338,400,401,402,403 Because the relative risk reduction is correlated with the degree of LDL lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits.400,401,402

When considering whether to initiate statin therapy for primary prevention, the 2018 AHA/ACC cholesterol management guideline recommends a shared decision-making approach between the patient and clinician.400 The guideline recommends consideration of statin therapy in certain high-risk groups such as adults 20-75 years of age with LDL-cholesterol levels ≥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%.400,401

The guideline states that patients with ASCVD should be treated with a statin in conjunction with lifestyle modification to reduce LDL-cholesterol concentrations.400 Because patients >75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects should be considered before initiating statin therapy in this population.400 The maximum tolerated intensity of a statin should be used to achieve optimum ASCVD benefits.400 AHA/ACC recommends the use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%).400 If high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) may be used.400

Intensity of Statin Therapy

The appropriate intensity of a statin should be used to reduce the risk of ASCVD.400 Based on the average LDL-cholesterol response observed with specific statins and dosages used in the randomized controlled studies evaluated by the AHA/ACC guideline panel, pitavastatin 1-4 mg daily is considered to be a moderate-intensity statin (producing approximate LDL-cholesterol reductions of 30-49%).400

Combination Antilipemic Therapy

The addition of a nonstatin drug (e.g., ezetimibe, PCSK9 inhibitor) may be useful in patients who experience an inadequate reduction in LDL-cholesterol concentrations despite maximally tolerated statin therapy (e.g., <50% reduction in LDL-cholesterol or LDL-cholesterol concentration ≥55 mg/dL or non-HDL-cholesterol ≥85 mg/dL).400,403 If combination therapy is necessary, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences.400,403

A 2022 consensus decision pathway published by ACC addresses the use of nonstatin therapies for primary or secondary prevention of ASCVD.403 In patients with primary hypercholesterolemia without ASCVD who require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 monoclonal antibody (mAb) are considered preferred initial nonstatin therapies due to demonstrated benefits in cardiovascular outcomes.403 If therapeutic goals are not achieved, other nonstatin therapies (e.g., inclisiran, bempedoic acid, evinacumab, lomitapide) may be considered.403

In patients receiving statin therapy as secondary prevention who are at very high risk of ASCVD and require additional LDL-lowering therapy despite maximal statin therapy, ezetimibe and/or a PCSK9 inhibitor are considered preferred initial nonstatin therapies.403 In patients receiving statin therapy as secondary prevention who are not at very high risk of ASCVD , ezetimibe is considered the preferred initial nonstatin therapy, followed by addition or replacement with a PCSK9 inhibitor if additional LDL-lowering therapy is needed.403 If therapeutic goals are not achieved in the secondary prevention setting, inclisiran (in place of a PCSK9 inhibitor) or bempedoic acid may be considered.403

A 2022 scientific statement published by the National Lipid Association (NLA) addresses the use of nonstatin therapies for ASCVD risk reduction in patients with statin intolerance.406 Nonstatin LDL-lowering therapy may be considered in patients with complete or partial statin intolerance, including during the course of attempting to identify a tolerable alternate statin regimen in patients with high or very high ASCVD risk.406 When nonstatin therapies are used, agents that have demonstrated cardiovascular outcome benefit in randomized trials are preferred.406

HIV Infection

Guidelines for the use of statin therapy in patients with HIV infection were developed by the Department of Health and Human Services in collaboration with the ACC, AHA, and HIV Medicine Association.503 These experts recommend at least moderate intensity statin therapy (i.e., pitavastatin 4 mg, atorvastatin 20 mg, or rosuvastatin 10 mg daily) for patients 40-75 years of age with HIV who have low-to-intermediate (<20%) 10-year ASCVD risk estimates.503 When 10-year ASCVD risk estimates are <5%, initiating at least moderate intensity statin therapy (i.e., pitavastatin 4 mg, atorvastatin 20 mg, or rosuvastatin 10 mg daily) may be considered, although the absolute benefit of such treatment may be modest.503 The decision to initiate a statin should take into account the presence or absence of HIV-related factors that can increase ASCVD risk.503 Data are insufficient to recommend for or against statin therapy as primary prevention of ASCVD in patients less than 40 years of age with HIV.503

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Administration !!navigator!!

Pitavastatin is administered orally once daily at any time of day, without regard to food.1,36

Store pitavastatin calcium tablets at 15-30°C; protect from light.1

Store pitavastatin magnesium tablets at 20-25°C; protect from moisture and light.36

Dosage !!navigator!!

Pitavastatin is commercially available in the US as pitavastatin calcium (e.g., Livalo®and generic equivalents) and pitavastatin magnesium (i.e., Zypitamag®).1,36 Commercially available tablets of Livalo® and Zypitamag® are considered to be bioequivalent.37,42

Dosages of pitavastatin calcium and pitavastatin magnesium are expressed in terms of pitavastatin.1,36

Dyslipidemias

Primary Hyperlipidemia

The recommended dosage range of pitavastatin for the management of primary hyperlipidemia or mixed dyslipidemia in adults is 2-4 mg once daily.1,36 The maximum dosage of pitavastatin is 4 mg once daily.1,36 An alternative LDL-cholesterol-lowering therapy is recommended for patients who are unable to achieve their LDL-cholesterol goal with pitavastatin 4 mg daily or who require a high-intensity statin.1,36

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

The recommended dosage of pitavastatin for the management of heterozygous familial hypercholesterolemia in children 8 years of age and older is 2-4 mg once daily.1 The maximum dosage of pitavastatin is 4 mg once daily.1

Reduction in Risk of Cardiovascular Events

The AHA/ACC cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk.400 The guideline recommends use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by at least 50%); if high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30-49%) should be used.400 The AHA/ACC guideline panel considers pitavastatin 1-4 mg daily to be a moderate-intensity statin.400

Dosage Modification for Concomitant Therapy

In patients receiving erythromycin concomitantly with pitavastatin, dosage of pitavastatin should not exceed 1 mg daily.1,36

In patients receiving rifampin concomitantly with pitavastatin, dosage of pitavastatin should not exceed 2 mg daily.1,36

Special Populations !!navigator!!

Renal Impairment

The recommended initial adult dosage of pitavastatin in patients with moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/minute per 1.73 m2 or 15-29 mL/minute per 1.73 m2 , respectively) or in patients with end-stage renal disease who are undergoing hemodialysis is 1 mg once daily.1,36 The maximum recommended dosage in these patients is 2 mg once daily.1,36 The manufacturers make no specific dosage recommendations for patients with mild renal impairment.1,36

Hepatic Impairment

The manufacturers make no specific dosage recommendations at this time for patients with hepatic impairment.1,36 Pitavastatin is contraindicated in patients with active liver failure or decompensated cirrhosis.1,36

Geriatric Patients

The manufacturers make no specific dosage recommendations at this time for geriatric patients.1,36 Dose selection in geriatric patients (≥65 years of age) should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.1,36

Pharmacogenomic Considerations

Solute carrier organic anion transporter (SLCO) 1B1 decreased or possible decreased function phenotype: Initial dosage ≤2 mg daily.500

SLCO1B1 poor function phenotype: Initial dosage ≤1 mg daily.500

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Musculoskeletal Effects

Myopathy manifested as muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK) and rhabdomyolysis may occur.1,36 Acute kidney injury secondary to myoglobinuria and rare fatalities has been reported in patients receiving statins, including pitavastatin.1 These adverse effects can occur at any dosage, but the risk increases with increasing dosa in clinical studies, the risk of severe myopathy increased with pitavastatin dosages exceeding 4 mg daily.1,36 The maximum recommended pitavastatin dosage is 4 mg once daily.1,36

Pitavastatin should be used with caution in patients with predisposing factors for myopathy (e.g., advanced age [65 years of age or older], renal impairment, inadequately treated hypothyroidism) and in patients receiving concomitant therapy with colchicine or certain antilipemic agents (e.g., fibric acid derivatives, antilipemic dosages of niacin).1,36 Pitavastatin is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil.1,36 There are pitavastatin dosage restrictions for patients taking erythromycin or rifampin.1,36

AHA/ACC cholesterol management guideline recommends measurement of CK levels in patients with severe statin-associated muscle symptoms; however, routine monitoring is not useful.400

Pitavastatin should be discontinued if CK concentrations become markedly elevated or if myopathy is diagnosed or suspected.1,36 Muscle symptoms and CK elevations may resolve if pitavastatin is discontinued.1,36 Pitavastatin therapy should be temporarily withheld in patients experiencing an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures).1,36

Immune-mediated Necrotizing Myopathy

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins, including reports of recurrence when the same or a different statin was administered.1,36 The condition is characterized by proximal muscle weakness and elevated CK concentrations that persist despite discontinuance of statin therapy, positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement following therapy with immunosuppressive agents.1,36 Additional neuromuscular and serologic testing may be necessary and treatment with immunosuppressive agents may be required in patients who develop IMNM.1,36

Discontinue pitavastatin if IMNM is suspected.1,36

Hepatic Effects

Increases in serum aminotransferase (i.e., AST, ALT) concentrations have been reported in patients receiving statins, including pitavastatin.1 These increases usually appeared soon after initiation, were transient and asymptomatic, and resolved or improved with continued therapy or after temporary interruption of therapy.1,36

Cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins, including pitavastatin, during postmarketing surveillance.1,36

Consider liver enzyme tests prior to initiation of pitavastatin therapy and repeated as clinically indicated.1,36 Serious statin-related liver injury is rare and unpredictable in individual patients, and routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.200 AHA/ACC cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver function tests in adults experiencing symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin or sclera); however, routine monitoring is not required.400

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, pitavastatin therapy should be promptly interrupted.1,36

Pitavastatin should be used with caution in patients who consume substantial amounts of alcohol.1,36 The drug is contraindicated in patients with active liver failure or decompensated cirrhosis.1,36

Hyperglycemic Effects

Increases in glycosylated hemoglobin (hemoglobin A1c [HbA1c]) and fasting serum glucose concentrations have been reported in patients receiving statins, including pitavastatin.1,200 Data from clinical trials and meta-analyses indicate that statin therapy may increase the risk of developing diabetes mellitus.200

AHA/ACC cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus; because the benefits of statin therapy outweigh the risks of new-onset diabetes, the possibility of this adverse effect should not be a contraindication to statin therapy or a reason for discontinuance of therapy.400

Specific Populations

Pregnancy

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit.405 This determination was based on several factors including safety signals from animal data.405 In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester.400 Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm.405 More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy; this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use.405 The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects.405 While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors.400,405 FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests limited potential for statins to cause malformations and other adverse embryofetal effects.405 Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins.405 While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits.400,405,402 Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.405

Lactation

It is not known whether pitavastatin is distributed into human milk; however, other statins have been shown to distribute into human milk.1,36 The effects of pitavastatin on breast-fed infants or milk production also are not known.1 Because of the potential for serious adverse reactions from the drug in breast-fed infants, the drug is not recommended in nursing women.1,36 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.400,405,402

Females and Males of Reproductive Potential

Pitavastatin had no adverse effects on male and female rat fertility at oral doses of 10 and 30 mg/kg per day, respectively, such systemic exposures are 56- and 354-times clinical exposure at 4 mg daily based on AUC.1,36 Pitavastatin treatment in rabbits resulted in mortality in males and females given 1 mg/kg per day (30-times clinical systemic exposure at 4 mg daily based on AUC) and higher during a fertility study.1,36 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.1,36

AHA/ACC cholesterol management guideline states women (including adolescents) of childbearing age who are sexually active should be counseled to use a reliable form of contraception.400

Pediatric Use

Safety and efficacy of pitavastatin calcium have not been established in pediatric patients younger than 8 years of age with heterozygous familial hypercholesterolemia (HeFH) or in pediatric patients with other types of hyperlipidemia.1

Safety and effectiveness of pitavastatin calcium as an adjunctive therapy to diet to reduce elevated LDL-cholesterol have been established in pediatric patients 8 years of age and older with HeFH.1 Use of pitavastatin for this indication is based on a 12-week, double-blind, placebo-controlled trial in 82 pediatric patients and a 52-week open-label trial in 85 pediatric patients with HeFH.1 In the double-blind trial, LDL-cholesterol, total cholesterol, non-HDL-cholesterol, and apo-B were reduced by 21-38, 16-30, 21-36, and 20-28%, respectively in pediatric patients 8-16 years of age treated with pitavastatin 1, 2, and 4 mg once daily.1 Such reductions, compared to placebo, were significant and dose dependent.1

Dose-dependent increases in pitavastatin plasma concentrations at trough (for 2 and 4 mg doses) and 1 hour post dose were observed in pediatric patients 8-16 years of age receiving pitavastatin caclium (1, 2, or 4 mg once daily).1 A dose-dependent increase in pitavastatin lactone plasma concentrations was observed at trough and 1 hour post dose.1

Safety and efficacy of pitavastatin magnesium have not been established in pediatric patients younger than 18 years of age.36

Geriatric Use

In clinical studies of pitavastatin, approximately 43% of patients were 65 years of age or older.1 No substantial differences in safety or efficacy relative to younger adults were observed, but increased sensitivity in some older patients cannot be ruled out.1,36 Data from a pharmacokinetic study indicate that peak plasma concentrations and AUC of pitavastatin were 10 and 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adults.1

Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects of statin therapy should be considered before initiating statin therapy in this population.400

Monitor geriatric patients for an increased risk of myopathy.1,36

Hepatic Impairment

Results of a pharmacokinetic study indicate that peak plasma concentrations or AUC of pitavastatin were 1.3- or 1.6-fold higher, respectively, in patients with mild (Child-Pugh class A) hepatic impairment compared with those in healthy individuals.1 In patients with moderate (Child-Pugh class B) hepatic impairment, peak plasma concentrations or AUC of pitavastatin were 2.7- or 3.8-fold higher, respectively, compared with those in healthy individuals.1 In this study, the mean elimination half-life of pitavastatin in healthy individuals, patients with mild hepatic impairment, or patients with moderate hepatic impairment was 8, 10, or 15 hours, respectively.1

Pitavastatin should be used with caution in patients with a history of liver disease (e.g., chronic alcoholic liver disease) and/or in patients who consume substantial amounts of alcohol.1,36 Pitavastatin is contraindicated in patients with active liver failure or decompensated cirrhosis.1,36

Renal Impairment

Peak plasma concentrations or AUC of pitavastatin were 60 or 102% higher, respectively, in patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/minute per 1.73 m2) compared with healthy individuals.1 In patients with severe renal impairment (eGFR 15-29 mL/minute per 1.73 m2) not undergoing hemodialysis, peak plasma concentrations or AUC of pitavastatin were 18 or 36% higher, respectively, compared with those in healthy individuals following a single 4-mg dose of pitavastatin; the mean percentage of non-protein bound pitavastatin was approximately 0.6% in both groups.1 In patients with end-stage renal disease (ESRD) undergoing hemodialysis, peak plasma concentrations or AUC of pitavastatin were 40 or 86% higher, respectively, compared with those in healthy individuals.1 Patients undergoing hemodialysis have a 33 or 36% increase in the mean unbound fraction of pitavastatin compared with healthy individuals or patients with moderate renal impairment, respectively.1 The effect of mild renal impairment on pitavastatin exposure has not been established.1,36

Dosage adjustments are required in patients with moderate renal impairment (estimated glomerular filtration [eGFR] rate 30-59 mL/minute per 1.73 m2), patients with severe renal impairment not undergoing hemodialysis (eGFR 15-29 mL/minute per 1.73 m2), and patients with ESRD undergoing hemodialysis.1,36

Renal impairment is a risk factor for myopathy and rhabdomyolysis; monitor all patients with renal impairment for development of myopathy.1,36

Pharmacogenomic Consideratons

Genetic variation in the solute carrier organic anion transporter (SLCO) family member (SLCO1B1), ABCG2 (also known as breast cancer resistance protein [BCRP]), and cytochrome P450 isoenzyme (CYP) 2C9 genes alter systemic exposure to statins (i.e., lovastatin, simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin), which can increase the risk for statin-associated musculoskeletal symptoms.500 SLCO1B1 encodes a transporter (SLCO1B1; alternative names include organic ion transporter protein [OATP] 1B1 or OATP-C) that facilitates the hepatic uptake of all statins.500 ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin and atorvastatin; CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins (e.g., fluvastatin).500

In patients with phenotypes that result in increased statin exposure, the potential for other patient-specific issues that may increase statin exposure (e.g., renal and hepatic function, drug-drug interactions) must also be considered.500 Experts state that given the balance of statin-associated musculoskeletal symptoms risk versus known cardiovascular disease benefit, for patients who are candidates for new statin therapy, pharmacogenetic test results may provide additional useful information.500

Pharmacogenetic test results may be used as the basis for changing to another statin type or dose for patients currently prescribed statin therapy, depending on how long the patient has been tolerating the statin.500 Experts state that statin therapy should neither be discontinued nor avoided based on SLCO1B1, ABCG2, or CYP2C9 genotype results for patients with an indication for statin therapy, especially if the statin therapy is based on the shared decision making between patient and provider.500

Patients with SLCO1B1 decreased or possible decreased function phenotypes or poor function phenotypes will have increased pitavastatin exposure compared to those with normal function, which may translate to an increased risk of statin-associated musculoskeletal symptoms.500 Patients with such phenotypes may require lower doses, an alternative statin, or combination therapy (i.e., pitavastatin plus a nonstatin guideline directed medical therapy).500

There are no data available regarding SLCO1B1 genotype effects on statin response or myopathy in pediatric patients.500

Common Adverse Effects !!navigator!!

Pitavastatin is commercially available in the US as pitavastatin calcium (e.g., Livalo®and generic equivalents) and pitavastatin magnesium (i.e., Zypitamag®).1,36 The main clinical studies with pitavastatin have been conducted with pitavastatin calcium, and the incidences of adverse effects reported are from clinical trials using the calcium salt.1,42 Because pitavastatin calcium and pitavastatin magnesium contain the same active moiety (pitavastatin), tolerability is expected to be similar between the 2 different salts.38,41,42

Adverse effects reported in 2% or more of patients receiving pitavastatin include myalgia, back pain, diarrhea, constipation, and pain in extremity.1

Drug Interactions ⬆ ⬇

[Section Outline]

Pitavastatin is minimally metabolized by cytochrome P-450 (CYP) isoenzyme 2C9 and, to a lesser extent, by CYP2C8.1,7,8

Pitavastatin is a substrate of P-glycoprotein (P-gp) and organic anion transporter protein (OATP) 1B1 and 1B3.339,501,502

Drugs Affecting or Affected by Transport Systems !!navigator!!

Pitavastatin is a substrate of P-glycoprotein (P-gp) and organic anion transporter protein (OATP) 1B1 and 1B3.7,8,30,339,501,502 Drugs that inhibit OATP1B1 (e.g., cyclosporine, erythromycin, rifampin), OATP1B3, or P-gp can increase bioavailability of pitavastatin and increase the risk of statin-induced toxicity (e.g., myopathy).1,7,8,9,30,33,339,501,502

Colchicine !!navigator!!

Myopathy, including rhabdomyolysis, has been reported in patients receiving various statins concomitantly with colchicine.1 Some experts state the combination is reasonable when clinically indicated and while closely monitoring patients for signs and symptoms of myopathy.339,502 The benefit of the combined use of pitavastatin with colchicine should be carefully weighed against the increased risk of myopathy and rhabdomyolysis.1,36,1,36

Digoxin !!navigator!!

Concomitant use of pitavastatin (4 mg once daily) and digoxin (0.25 mg once daily for 7 days) decreased pitavastatin peak plasma concentration by 9%, increased pitavastatin AUC by 4%, and decreased digoxin peak plasma concentration and AUC by 4 and 3%, respectively.1

Diltiazem !!navigator!!

Concomitant use of pitavastatin (4 mg once daily on days 1-5 and 11-15) and extended-release diltiazem hydrochloride (240 mg on days 6-15) increased pitavastatin peak plasma concentration and AUC by 15 and 10%, respectively, and decreased diltiazem peak plasma concentration and AUC by 7 and 2%, respectively.1

Enalapril !!navigator!!

Concomitant use of pitavastatin (4 mg once daily) and enalapril (20 mg once daily for 5 days) increased AUC of pitavastatin by 6% and decreased peak plasma concentrations of the drug by 7%.1 Peak plasma concentrations and AUC of enalapril were increased by 12%.1

Erythromycin !!navigator!!

Erythromycin substantially increases pitavastatin exposure.1 Following concomitant use of pitavastatin (4 mg as a single dose on day 4) and erythromycin (500 mg 4 times daily for 6 days), pitavastatin peak plasma concentration and AUC were increased by 3.6- and 2.8-fold, respectively; such effects were considered clinically important.1 The interaction between pitavastatin and erythromycin probably resulted partly from erythromycin-induced inhibition of OATP1B1-mediated hepatic uptake of pitavastatin.9,30 If used concomitantly with erythromycin, dosage of pitavastatin should not exceed 1 mg once daily.1,36

Ezetimibe !!navigator!!

Concomitant use of pitavastatin (2 mg once daily) and ezetimibe (10 mg for 7 days) decreased pitavastatin peak plasma concentration and AUC by 0.2 and 2%, respectively, and increased ezetimibe peak plasma concentration and AUC by 2 and 9%, respectively.1

Fibric Acid Derivatives !!navigator!!

Concomitant use of statins and gemfibrozil increases the risk of myopathy and rhabdomyolysis.1,36 Following concomitant use of pitavastatin (4 mg once daily) and gemfibrozil (600 mg twice daily for 7 days), pitavastatin peak plasma concentration and AUC were increased by 31 and 45%, respectively.1

Concomitant use of statins and other fibric acid derivatives (e.g., fenofibrate) increases the risk of myopathy and rhabdomyolysis.1,36 Following concomitant use of pitavastatin (4 mg once daily) and fenofibrate (160 mg once daily for 7 days), pitavastatin peak plasma concentration and AUC were increased by 11 and 18%, respectively.1

The manufacturers state that concomitant use of pitavastatin and gemfibrozil should be avoided , and concomitant use with other fibric acid derivatives (e.g., fenofibrate) may be considered if the benefit of combined use outweighs the increased risk of myopathy and rhabdomyolysis.1,36 Experts state it is safer to use fenofibrate than gemfibrozil because of a lower risk of severe myopathy.400

Grapefruit Juice !!navigator!!

Concomitant use of pitavastatin (2 mg as a single dose on day 3) and grapefruit juice (for 4 days) decreased pitavastatin peak plasma concentration by 12% and increased pitavastatin AUC by 15%.1

HIV Protease Inhibitors !!navigator!!

Atazanavir

Concomitant use of pitavastatin (4 mg once daily) and atazanavir (300 mg once daily for 5 days) increased peak plasma concentrations and AUC of pitavastatin by 60 and 31%, respectively, and atazanavir by 13 and 6%, respectively.1,503 Some experts state that dosage adjustments are not necessary when pitavastatin is used concomitantly with atazanavir.503

Darunavir

Concomitant use of pitavastatin (4 mg once daily on days 1-5 and 12-16) and ritonavir-boosted darunavir (darunavir 800 mg with ritonavir 100 mg once daily on days 6-16) decreased peak plasma concentration and AUC of pitavastatin by 4 and 26%, respectively, while increasing peak plasma concentration and AUC of darunavir by 6 and 3%, respectively, and ritonavir by 2 and 8%, respectively.1,503 Some experts state that dosage adjustments are not necessary when pitavastatin is used concomitantly with ritonavir-boosted darunavir.503

Lopinavir

Concomitant use of pitavastatin (4 mg once daily on days 1-5 and 20-24) and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir; lopinavir 400 mg/ritonavir 100 mg twice daily on days 9-24) decreased peak plasma concentration and AUC of pitavastatin by 4 and 20%, respectively, lopinavir by 7 and 9%, respectively, and ritonavir by 11 and 11%, respectively.1,503 Some experts state that dosage adjustments are not necessary when pitavastatin is used concomitantly with lopinavir/ritonavir.503

Immunosuppressive Agents !!navigator!!

Cyclosporine substantially increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis.1,339 Following concomitant use of pitavastatin (2 mg once daily for 6 days) and cyclosporine (2 mg/kg on day 6), pitavastatin peak plasma concentration and AUC were increased by 6.6- and 4.6-fold, respectively; such effects were considered clinically important.1 The interaction between pitavastatin and cyclosporine probably resulted partly from cyclosporine-induced inhibition of OATP1B1-mediated hepatic uptake of pitavastatin.7,8,9,30,33 Because of the potential for substantial increases in pitavastatin exposure, concomitant use of pitavastatin with cyclosporine is contraindicated .1,36

Although data are more limited with everolimus, sirolimus, and tacrolimus, the drug interaction potential of these other immunosuppressive agents is expected to be similar to that of cyclosporine because of similar metabolism; therefore, some experts recommend that these drugs should also be avoided in patients receiving pitavastatin.339

Itraconazole !!navigator!!

Concomitant use of pitavastatin (4 mg as a single dose) and itraconazole (200 mg once daily for 5 days) decreased pitavastatin peak plasma concentration and AUC by 22 and 23%, respectively.1

Niacin !!navigator!!

Concomitant use of pitavastatin and antilipemic dosages (1 g daily or higher) of niacin increases the risk of myopathy and rhabdomyolysis.1,36

The manufacturer states concomitant use of pitavastatin with lipid-modifying doses (≥1 g/day) of niacin may be considered if the benefit of combined use outweighs the increased risk of myopathy and rhabdomyolysis.1,36

Rifampin !!navigator!!

Rifampin substantially increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis.1 Following concomitant use of pitavastatin (4 mg once daily) and rifampin (600 mg once daily for 5 days), pitavastatin peak plasma concentration and AUC were increased by twofold and 29%, respectively, and rifampin peak plasma concentration and AUC were decreased by 18 and 15%, respectively.1 The increase in pitavastatin peak plasma concentration is considered clinically important1 and probably resulted partly from inhibition of OATP1B1-mediated hepatic uptake of pitavastatin.30,33 If used concomitantly with rifampin, dosage of pitavastatin should not exceed 2 mg once daily.1,36

Warfarin !!navigator!!

Pitavastatin had no clinically important pharmacokinetic interaction with R - and S -warfarin.1 Following concomitant use of pitavastatin (4 mg once daily for 9 days) and an individualized maintenance dosage of warfarin sodium (2-7 mg for 8 days), R -warfarin peak plasma concentration and AUC increased by 3 and 7%, respectively, and S -warfarin peak plasma concentration and AUC increased by 3 and 6%, respectively.1 In addition, pitavastatin (4 mg once daily) had no clinically important effect on prothrombin time (PT) and international normalized ratio (INR) in patients receiving long-term warfarin therapy; however, the manufacturer and some experts recommend close monitoring of PT and INR after pitavastatin is initiated and whenever there is a change in the statin dosage in patients receiving warfarin.1,36,339

Other Information ⬆ ⬇

Description

Pitavastatin calcium and pitavastatin magnesium are synthetic antilipemic agents.1,36,501 Pitavastatin is a competitive inhibitor of 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate (an early and rate-limiting step in cholesterol biosynthesis).1,7,8,36 Inhibition of HMG-CoA reductase results in reduction of hepatic cholesterol biosynthesis, which leads to a compensatory increase in the expression of low-density lipoprotein (LDL) receptors on hepatic cell surfaces and, subsequently, increased hepatic clearance of LDL-cholesterol from blood.1,7,8,36 Pitavastatin reduces serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and increases serum high-density lipoprotein (HDL)-cholesterol concentrations in patients with primary hypercholesterolemia or mixed dyslipidemia.1,3,4,5,6,36 Sustained inhibition of cholesterol biosynthesis in the liver also decreases very low-density lipoprotein (VLDL)-cholesterol concentrations.1,36 Other favorable effects of statins (pleitropic effects) include an antiproliferative effect on smooth muscle cells, reconstruction of endothelial activity, antioxidant, antithrombotic, anticancer, and anti-inflammatory effects.501

Pitavastatin is absorbed in the small intestine (very small amounts from the colon); peak plasma concentrations are attained in approximately 1 hour.1 Peak plasma concentration and AUC increased in an approximately dose-proportional manner for single doses of 1-24 mg and did not differ following evening or morning drug administration.1 Percent change from baseline for LDL-cholesterol following evening dosing was slightly greater than that following morning dosing in healthy volunteers receving pitavastatin 4 mg.1 Administration of pitavastatin calcium with a high fat meal (50% fat content) decreases pitavastatin peak plasma concentration by 43%; AUC was not significantly reduced.1 Administration of pitavastatin magnesium with a high fat meal (50% fat content) decreases pitavastatin peak plasma concentration by 39%; AUC was not significantly reduced.37 Pitavastatin calcium tablets (Livalo®) are bioequivalent to pitavastatin magnesium tablets (Zypitamag®) under fasting conditions.37,42 LDL-cholesterol response to therapy may be assessed as early as 4 weeks after pitavastatin initiation.1

Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein.1 Pitavastatin is unlikely to be removed by hemodialysis because of such protein binding.1 Patients undergoing hemodialysis have a 33 or 36% increase in the mean unbound fraction of pitavastatin compared with healthy individuals or patients with moderate renal impairment, respectively.1 Pitavastatin crosses the placenta in rats; there is no available information about the presence of pitavastatin in human or animal milk.1

Pitavastatin undergoes carrier-mediated uptake into hepatocytes, principally via organic anionic transport polypeptide (OATP) 1B1 (OATP2) and, to a lesser extent, by OATP1B3 and OATP2B1;7,8,33,501 hepatic uptake of pitavastatin is required for pharmacologic effects.7 Pitavastatin is 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 The drug is minimally metabolized by cytochrome P-450 (CYP) microsomal isoenzymes 2C9 and 2C8.1,7,8 The mean plasma elimination half-life of pitavastatin is approximately 12 hours.1 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

Following oral administration of pitavastatin, approximately 79 or 15% of the dose is excreted in feces or urine, respectively, within 7 days.1

Data from a pharmacokinetic study indicate that peak plasma concentrations and AUC of pitavastatin were 60 and 54% higher, respectively, in healthy females compared with healthy males.1

Data from a pharmacokinetic study indicate that peak plasma concentrations and AUC of pitavastatin were 21 and 5% lower, respectively, in Black or African American healthy volunteers compared with those of white healthy volunteers.1 Data from a pharmacokinetic study indicate there were no significant differences in peak plasma concentrations or AUC of pitavastatin in white and Japanese volunteers.1

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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

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

Pitavastatin Magnesium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg (of pitavastatin)

Zypitamag®

Medicure

4 mg (of pitavastatin)*

Zypitamag®

Medicure

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

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions September 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

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

References ⬆

1. Kowa Pharmaceuticals America, Inc. Livalo® (pitavastatin calcium) tablets prescribing information. Montgomery, AL; 2024 Jan.

3. Budinski D, Arneson V, Hounslow N, Grasiansky N. Pitavastatin compared with atorvastatin in primary hypercholesterolemia or combined dyslipidemia. Clin Lipidol . 2009; 4:291-302.

4. Ose L, Budinski D, Hounslow N et al. Comparison of pitavastatin with simvastatin in primary hypercholesterolaemia or combined dyslipidaemia. Curr Med Res Opin . 2009; 25:2755-64. [PubMed 19785568]

5. Stender S, Hounslow N. Robust efficacy of pitavastatin and comparable safety to pravastatin. Atherosclerosis Suppl . 2009; 10:945, abstract P770.

6. Ose L, Budinski D, Hounslow N et al. Long-term treatment with pitavastatin is effective and well tolerated by patients with primary hypercholesterolemia or combined dyslipidemia. Atherosclerosis . 2010; 210:202-8. [PubMed 20080236]

7. Wensel TM, Waldrop BA, Wensel B. Pitavastatin: a new HMG-CoA reductase inhibitor. Ann Pharmacother . 2010; 44:507-14. [PubMed 20179258]

8. Saito Y. Critical appraisal of the role of pitavastatin in treating dyslipidemias and achieving lipid goals. Vasc Health Risk Manag . 2009; 5:921-36. [PubMed 19997573]

9. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 22-363: Summary Review. From FDA website. 2009 Aug 3. [Web]

13. Herd JA, Ballantyne CM, Farmer JA et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol . 1997; 80:278-86. [PubMed 9264419]

14. MAAS Investigators. Effect of simvastatin on coronary atheroma: the multicentre anti-atheroma study (MAAS). Lancet . 1994; 344:633-8. [PubMed 7864934]

15. Pitt B, Mancini GBJ, Ellis SG et al. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol . 1995; 26:1133-9. [PubMed 7594023]

16. Crouse JR III, Byington RP, Bond MG et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol . 1995; 75:455-9. [PubMed 7863988]

17. Jukema JW, Bruschke AVG, van Boven AJ et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation . 1995; 91:2528-40. [PubMed 7743614]

18. Salonen R, Nyyssonen K, Porkkala-Sarataho E et al. The Kuopio Atherosclerosis Prevention Study (KAPS): Effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression. Am J Cardiol . 1995; 76:34-9C.

19. Blankenhorn DH, Azen SP, Kramsch DM et al. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). The MARS Research Group. Ann Intern Med. 1993; 119:969-76.

20. Waters D, Higginson L, Gladstone P et al. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) Substudy. Circulation. 1995; 92:2404-10.

21. Brown G, Albers JJ, Fisher LD et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med . 1990; 323:1289-98. [PubMed 2215615]

22. Furberg CD, Adams HP, Applegate WB et al for the Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation . 1994; 90:1679-87. [PubMed 7734010]

23. DeGroot E, Jukema JW, Montauban AD et al. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol . 1998; 31:1561-7. [PubMed 9626835]

24. Glorioso N, Troffa C, Filigheddu F et al. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension . 1999; 34:1281-6. [PubMed 10601131]

25. Borghi C, Prandin MG, Costa FV et al. Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia. J Cardiovasc Pharmacol . 2000; 35:549-55. [PubMed 10774784]

26. Ridker PM, Rifai N, Pfeffer MA et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation . 1999; 100:230-5. [PubMed 10411845]

27. Kluft C, de Maat MPM, Leuven JAG et al. Statins and C-reactive protein. Lancet . 1999; 353:1274-5.

30. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol . 2009; 158:693-705. [PubMed 19785645]

33. Hirano M, Maeda K, Shitara Y et al. Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos . 2006; 34:1229-36. [PubMed 16595711]

36. Medicure. Zypitamag® (pitavastatin magnesium) tablets prescribing information. Princeton, NJ; 2024 Jan.

37. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208379Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

38. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry. Applications covered by section 505(b)(2). October 1999. From FDA website [Web]

39. Food and Drug Administration. Approval letter for pitavastatin magnesium (NDA 208379) for Zydus Pharmaceuticals (USA) Inc. 2017 Jul 14.

40. Approved Drug Products with Therapeutic Equivalence Evaluations (Electronic Orange Book). Accessed 2018 Jun. From FDA website.[Web][Web]

41. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208379Orig1s000: Other review(s). From FDA website. [Web]

42. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208379Orig1s000: Summary review. From FDA website. [Web]

43. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 22-363: Medical review. From FDA website.[Web]

45. Stender S, Budinski D, Hounslow N. Pitavastatin demonstrates long-term efficacy, safety and tolerability in elderly patients with primary hypercholesterolaemia or combined (mixed) dyslipidaemia. Eur J Prev Cardiol. 2013 Feb;20(1):29-39. doi: 10.1177/2047487312437326. Epub 2012 Jan 23. PMID: 22345687.

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