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Pitavastatin

Pronunciation

(pi TA va sta tin)

Index Terms

  • Pitavastatin Calcium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Livalo: 1 mg, 2 mg, 4 mg

Brand Names: U.S.

  • Livalo

Pharmacologic Category

  • Antilipemic Agent, HMG-CoA Reductase Inhibitor

Pharmacology

Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects (de Denus, 2002; Ray, 2005).

Distribution

Vd: ~148 L

Metabolism

Hepatic, via UGT1A3 and UGT 2B7; minimal metabolism via CYP2C9 and CYP2C8

Excretion

Feces (79%); urine (15%)

Time to Peak

~1 hour

Half-Life Elimination

~12 hours

Protein Binding

>99%

Special Populations: Renal Function Impairment

AUC and Cmax were 79% and 60% higher in patients with CrCl 30 to 60 mL/min and 86% and 40% higher in patients with ESRD on hemodialysis, respectively. The effect of mild and severe renal impairment on exposure is not known.

Special Populations: Hepatic Function Impairment

Half-life was 15, 10, and 8 h for patients with moderate hepatic impairment, mild hepatic impairment, and healthy hepatic function, respectively.

Special Populations: Elderly

Cmax and AUC were 10% and 30% higher, respectively, in elderly patients compared with younger patients.

Special Populations: Gender

Cmax and AUC were 60% and 54% higher, respectively, in women compared with men.

Special Populations: Race

Cmax and AUC were 60% and 54% higher, respectively, in women compared with men.

Use: Labeled Indications

Primary hyperlipidemia and mixed dyslipidemia: Adjunct to dietary therapy to reduce elevations in total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and triglycerides (TG), and to increase low HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia

Use: Unlabeled

Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) according to the American College of Cardiology/American Heart Association: To reduce the risk of ASCVD in patients with clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) who are greater than 75 years of age or not a candidate for high-intensity statin therapy; in patients without clinical ASCVD if LDL-C is 190 mg/dL or greater and not a candidate for high-intensity statin therapy; in patients without clinical ASCVD who have type 1 or type 2 diabetes and are between 40 and 75 years of age; in patients with an estimated 10-year ASCVD risk 7.5% or greater and who are between 40 and 75 years of age (Stone, 2013). Specific recommendations from the Kidney Disease: Improving Global Outcomes (KDIGO) organization have also been released for patients with chronic kidney disease (KDIGO [Tonelli, 2013]).

Contraindications

Hypersensitivity to pitavastatin or any component of the formulation; active liver disease including unexplained persistent elevations of hepatic transaminases; concurrent use with cyclosporine; pregnancy; breast-feeding

Dosing: Adult

Primary hyperlipidemia and mixed dyslipidemia: Oral: Initial: 2 mg once daily; may be increased to maximum 4 mg once daily

Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and patient response; adjustments should be made at intervals of 4 weeks.

Prevention of cardiovascular disease (off-label use): ACC/AHA Blood Cholesterol Guideline recommendations to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) (Stone, 2013): Adults ≥21 years: Oral:

Primary prevention:

LDL-C ≥190 mg/dL: High intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Type 1 or 2 diabetes and age 40-75 years: Moderate intensity therapy: 2-4 mg once daily

Type 1 or 2 diabetes, age 40-75 years, and an estimated 10-year ASCVD risk ≥7.5%: High intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Age 40-75 years and an estimated 10-year ASCVD risk ≥7.5%: Moderate to high intensity therapy: 2-4 mg once daily or consider using high intensity statin therapy (eg, atorvastatin or rosuvastatin)

Secondary prevention:

Patient has clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) or is post-CABG (AHA [Kulik, 2015]) and:

Age ≤75 years: High intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Age >75 years or not a candidate for high intensity therapy: Moderate intensity therapy: 2-4 mg once daily

Dosage adjustment with concomitant medications:

Erythromycin: Pitavastatin dose should not exceed 1 mg once daily

Rifampin: Pitavastatin dose should not exceed 2 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 15-60 mL/minute/1.73 m2 (not receiving hemodialysis): Initial: 1 mg once daily; maximum: 2 mg once daily

ESRD: Initial: 1 mg once daily; maximum: 2 mg once daily

Dosing: Hepatic Impairment

Contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.

Dosing: Adjustment for Toxicity

Severe muscle symptoms or fatigue: Promptly discontinue use; evaluate CPK, creatinine, and urinalysis for myoglobinuria (Stone, 2013).

Mild to moderate muscle symptoms: Discontinue use until symptoms can be evaluated; evaluate patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution, resume the original or lower dose of pitavastatin. If muscle symptoms recur, discontinue pitavastatin use. After muscle symptom resolution, may then use a low dose of a different statin; gradually increase if tolerated. In the absence of continued statin use, if muscle symptoms or elevated CPK continues after 2 months, consider other causes of muscle symptoms. If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (Stone, 2013).

Administration

May be administered with or without food; may take without regard to time of day.

Dietary Considerations

May be taken with or without food; may take without regard to time of day. Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects (Lapi, 2008; Smith, 2003).

Storage

Store at controlled room temperature of 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Acipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Monitor therapy

Antacids: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Monitor therapy

Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Monitor therapy

Atazanavir: May increase the serum concentration of Pitavastatin. Monitor therapy

Bezafibrate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors. More specifically, bezafibrate may increase the serum concentration of fluvastatin Management: Monitor patients closely for myopathy with concomitant use of bezafibrate and HMG-CoA reductase inhibitors. Concomitant use is contraindicated in patients predisposed to myopathy and alternative therapy should be considered. Consider therapy modification

Boceprevir: May increase the serum concentration of Pitavastatin. Monitor therapy

Ciprofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Management: Avoid the use of HMG-CoA reductase inhibitors and ciprofibrate if possible. If concomitant therapy is considered, benefits should be carefully weighed against the risks, and patients should be monitored closely for signs/symptoms of muscle toxicity. Consider therapy modification

Clarithromycin: May increase the serum concentration of Pitavastatin. Monitor therapy

Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Consider therapy modification

CycloSPORINE (Systemic): May increase the serum concentration of Pitavastatin. Avoid combination

Daclatasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Monitor therapy

Danazol: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Concurrent use of simvastatin with danazol is contraindicated. Initiate lovastatin at an adult maximum dose of 10 mg/day, and do not exceed 20 mg/day, when danazol is given concomitantly. Fluvastatin, pravastatin and rosuvastatin may pose lower risk. Consider therapy modification

DAPTOmycin: HMG-CoA Reductase Inhibitors may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Erythromycin (Systemic): May increase the serum concentration of Pitavastatin. Management: Limit pitavastatin to a maximum of 1 mg/day (adult dose) when used in combination with erythromycin. If this combination is used, monitor patients more closely for evidence of pitavastatin toxicity. Consider therapy modification

Fenofibrate and Derivatives: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Monitor therapy

Fusidic Acid (Systemic): May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Specifically, the risk for muscle toxicities, including rhabdomyolysis may be significantly increased. Management: Avoid concurrent use whenever possible. Use is listed as contraindicated in product characteristic summaries in several countries, although UK labeling suggests that use could be considered under exceptional circumstances and with close supervision. Avoid combination

Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of Pitavastatin. Gemfibrozil may increase the serum concentration of Pitavastatin. Avoid combination

Lanthanum: HMG-CoA Reductase Inhibitors may decrease the serum concentration of Lanthanum. Management: Administer HMG-CoA reductase inhibitors at least two hours before or after lanthanum. Consider therapy modification

Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Management: Greatest concern with niacin 1 g/d or greater. Avoid simvastatin 80 mg with niacin 1 g or greater in Chinese patients. Do not exceed 40 mg/d of simva or lovastatin with Niaspan. Use of niacin with rosuvastatin 40 mg is contraindicated (Canadian label). Consider therapy modification

Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Pitavastatin. Management: Canadian product labeling recommends use of the lowest pitavastatin dose with this combination. Monitor therapy

PAZOPanib: HMG-CoA Reductase Inhibitors may enhance the hepatotoxic effect of PAZOPanib. Specifically, the risk for increased serum transaminase concentrations may be increased. Management: Simvastatin is specifically implicated in the interaction. There is a lack of data regarding risk with other statins, but caution appears warranted with any statins. Atorvastatin should be avoided due to P-gp inhibition. Monitor therapy

Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Monitor therapy

Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Avoid combination

Rifamycin Derivatives: May increase the serum concentration of Pitavastatin. Management: Limit pitavastatin dose to a maximum of 2 mg/day with concurrent rifampin. Consider therapy modification

Sacubitril: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Monitor therapy

Simeprevir: May increase the serum concentration of Pitavastatin. Monitor therapy

Telaprevir: May increase the serum concentration of Pitavastatin. Monitor therapy

Telithromycin: May increase the serum concentration of Pitavastatin. Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Trabectedin: HMG-CoA Reductase Inhibitors may enhance the myopathic (rhabdomyolysis) effect of Trabectedin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

2% to 10%:

Gastrointestinal: Constipation (2% to 4%), diarrhea (2% to 3%)

Neuromuscular & skeletal: Back pain (1% to 4%), myalgia (2% to 3%), pain in extremities (1% to 2%)

<2% (Limited to important or life-threatening): Alkaline phosphatase increased, amnesia (reversible), arthralgia, bilirubin increased, blood glucose increased, cognitive impairment (reversible), confusion (reversible), CPK increased, glycosylated hemoglobin (Hb A1c) increased, headache, hyperglycemia, influenza, memory disturbance (reversible), memory impairment (reversible), nasopharyngitis, pruritus, rash, transaminases increased, urticaria

Additional class-related events or case reports (not necessarily reported with pitavastatin therapy): Cataracts, cirrhosis, dermatomyositis, eosinophilia, extraocular muscle movement impaired, fulminant hepatic necrosis, gynecomastia, hypersensitivity syndrome (symptoms may include anaphylaxis, angioedema, arthralgia, erythema multiforme, eosinophilia, hemolytic anemia, immune-mediated necrotizing myopathy (IMNM), interstitial lung disease, lupus syndrome, photosensitivity, polymyalgia rheumatica, positive ANA, purpura, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, vasculitis), ophthalmoplegia, peripheral nerve palsy, rhabdomyolysis, renal failure (secondary to rhabdomyolysis), thyroid dysfunction, tremor, vertigo

Warnings/Precautions

Concerns related to adverse effects:

• Diabetes mellitus: Increases in HbA1c and fasting blood glucose have been reported with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia.

• Hepatotoxicity: Postmarketing reports of fatal and nonfatal hepatic failure are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy. If an alternate etiology is not identified, do not restart pitavastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.

• Immune-mediated necrotizing myopathy (IMNM): IMNM, an autoimmune-mediated myopathy, has been reported (rarely) with HMG-CoA reductase inhibitor therapy. IMNM presents as proximal muscle weakness with elevated CPK levels, which persists despite discontinuation of HMG-CoA reductase inhibitor therapy; additionally, muscle biopsy may show necrotizing myopathy with limited inflammation. Immunosuppressive therapy (eg, corticosteroids, azathioprine) may be used for treatment.

• Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of erythromycin, protease inhibitors, fibric acid derivatives (eg, gemfibrozil), or niacin (doses ≥1 g/day) (see Drug Interactions). If concurrent use of erythromycin is warranted, dose adjustment of pitavastatin may be required. Ensure patient is on the lowest effective pitavastatin dose in all circumstances. Discontinue use with marked elevations of creatine kinase levels or diagnosis/suspicion of myopathy. Use caution in patients with renal impairment, inadequately treated hypothyroidism, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.

Disease-related concerns:

• Hepatic impairment and/or ethanol use: Use is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases; use with caution in patients who consume large amounts of ethanol or have a history of liver disease. May cause hepatic dysfunction. In all patients, liver function must be monitored prior to initiation of therapy; repeat LFTs if clinically indicated thereafter.

• Renal impairment: Dosage adjustment required in patients with a CrCl <60 mL/minute/1.73 m2 including end-stage renal disease receiving hemodialysis.

Concurrent drug therapy issues:

• Cyclosporine: Cyclosporine significantly increases pitavastatin levels and exposure. Concomitant use of cyclosporine is contraindicated.

Special Populations:

• Elderly: Use with caution in patients with advanced age, these patients are predisposed to myopathy.

• Surgical patients: The manufacturer recommends temporary discontinuation for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based on current research and clinical guidelines (Fleisher, 2009), HMG-CoA reductase inhibitors should be continued in the perioperative period. Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.

Other warnings/precautions:

• Appropriate use: Secondary causes of hyperlipidemia should be ruled out prior to therapy. Pitavastatin has not been studied when the primary lipid abnormality is chylomicron elevation (Fredrickson types I and V) or in familial dysbetalipoproteinemia (Fredrickson type III).

Monitoring Parameters

2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone, 2013):

Lipid panel (total cholesterol, HDL, LDL, triglycerides): Baseline lipid panel; fasting lipid profile within 4 to 12 weeks after initiation or dose adjustment and every 3 to 12 months (as clinically indicated) thereafter. If 2 consecutive LDL levels are <40 mg/dL, consider decreasing the dose.

Hepatic transaminase levels: Baseline measurement of hepatic transaminase levels (ie, ALT); measure hepatic function if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of skin or sclera) during therapy.

CPK: CPK should not be routinely measured. Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy). May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness, stiffness, cramping, weakness, or generalized fatigue).

Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy and encourage adherence to a heart-healthy diet, physical activity, a healthy body weight, and tobacco cessation.

If patient develops a confusional state or memory impairment, may evaluate patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.

Manufacturer's labeling: Liver enzyme tests at baseline and repeated when clinically indicated. Upon initiation or titration, lipid panel should be analyzed after 4 weeks of therapy.

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. There are reports of congenital anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy; however, maternal disease, differences in specific agents used, and the low rates of exposure limit the interpretation of the available data (Godfrey, 2012; Lecarpentier, 2012). Cholesterol biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase normally during pregnancy. The discontinuation of lipid lowering medications temporarily during pregnancy is not expected to have significant impact on the long term outcomes of primary hypercholesterolemia treatment.

Use of pitavastatin is contraindicated in pregnancy. HMG-CoA reductase inhibitors should be discontinued prior to pregnancy (ADA, 2013). If treatment of dyslipidemias is needed in pregnant women or in women of reproductive age, other agents are preferred (Berglund, 2012; Stone, 2013). The manufacturer recommends administration to women of childbearing potential only when conception is highly unlikely and patients have been informed of potential hazards.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, constipation, or diarrhea. Have patient report immediately to prescriber urinary retention, oliguria, signs of severe muscle problems, or signs of hepatic impairment (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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