Daewoong Pharmaceutical


Zuellig Pharma


Full Prescribing Info
Pitavastatin calcium.
Pharmacology: Pharmacodynamics: Pitavastatin is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) which is the key enzyme responsible for conversion of HMG-CoA to mevalonate. This target reaction is an early rate-limiting step in cholesterol biosynthesis. By blocking this enzyme, pitavastatin markedly reduce plasma concentrations of low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) and to a lesser extent apolipoprotein B (Apo-B) and triglycerides (TGs) as well as increase levels of high density lipoprotein cholesterol (HDLC) in patients with primary hypercholesterolemia or mixed dyslipidemia.
The mechanism of LDL-C lowering action may involve both reduction of very low density lipoprotein (VLDL) synthesis and increasing of LDL-C receptors. These reactions lead to reduced production and/or increased uptake and catabolism of LDL-C. Pitavastatin is an active molecule that not requires bioactivation after oral administration. Lipid-lowering effects were seen within 1-2 weeks and maximum therapeutic efficacy occurred within 4-6 weeks. Reductions in blood LDL-C concentrations were dose-dependent.
Pharmacokinetics: Absorption: The bioavailability of pitavastatin is 51%. Pitavastatin peak plasma concentrations (Cmax) occurre at 1 hour after oral administration. Coadministration of pitavastatin and food decreased rate of pitavastatin absorption by 43%, but does not significantly reduce the extent of absorbed pitavastatin. Plasma concentration of pitavastatin is higher in elderly (approximately 30% for area under the concentration-time curve [AUC]). Rate and extent of pitavastatin absorption are increased by 60% and 79%, respectively, in patients with moderate renal impairment.
Distribution: Pitavastatin is uptaken into hepatocytes by organic anionic transport polyppeptide (OATP) 1B1, 1B3, and 2B1. Hepatic uptake of pitavastatin is required for pharmacologic effects. More than 99% of serum pitavastatin is bound to serum protein. Data regarding distribution of pitavastatin into certain tissues are limited. Pitavastatin is distributed into breast milk in rats, but unknown in human. Because of the potential serious adverse reactions in breast-feeding infants, caution women this drug not to breast-feed their infants.
Metabolism and Elimination: Pitavastatin has a unique metabolic profile compared to other statins that contributes to a longer duration of action and a higher safety profile due to less drug-drug interactions. Pitavastatin is mostly metabolized by uridine 5'-diphosphae (UDP) glucuronosyltransferase (e.g. UGT1A1, UGT1A3, and UGT2B7) to an ester-type pitavastatin glucoronide conjugate and further metabolized to the inactive pitavastatin lactone metabolite. Small proportion of pitavastatin is metabolized by cytochrome P450 (CYP) hepatic enzymes, mainly 2C9 and 2C8. Mean plasma elimination half-life of pitavastatin is approximately 12 hours. 79% or 15% of oral administered solution of pitavastatin is excreted in feces and urine, respectively, within 7 days.
Pharmacokinetics Study in 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. 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.
Hypercholesterolemia, Familial hypercholesterolemia.
Precaution related to indications: Administration of this drug should only be considered after conducting a thorough physical examination and confirming the diagnosis is hypercholesterolemia or familial hypercholesterolemia.
Since there is no experience of use in homozygous causes of familial hypercholesterolemia, administration of this drug should be considered as a treatment supplement to non-drug therapy such as LDL-apheresis only when treatment with this drug is judged indispensable.
Dosage/Direction for Use
The usual dosage for an adult is 1-2 mg of pitavastatin calcium once daily after an evening meal. The dosage may be adjusted according to the patient's age and symptoms. When lowering of the LDL cholesterol level is insufficient, the dosage may be increased to a maximum of 4 mg per day.
Precautions relate to Dosage and Administration: In the case of administration to patients with hepatic disorders, the starting dose should be set to 1 mg per day and the maximal dose should be 2 mg per day (see Precautions and Pharmacology: Pharmacokinetics under Actions).
In the case of an increase in dosage of this drug, rhabdomyolysis-related adverse events may occur, When the dosage is increased to 4 mg some attention should be given to early signs of rhabdomyolysis such as CK (CPK) elevation, myoglobinuria, myalgia and weakness. (In overseas clinical studies, doses of 8 mg or above were discontinued due to several cases of rhabdomyolysis and related adverse events.)
There is no known specific treatment in the event of overdose of pitavastatin. In the episode of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis is unlikely to be of advantage due to high protein binding ratio of pitavastatin.
Known hypersensitivity to pitavastatin or any ingredients in the formulation. Active liver disease, including unexplained, persistent elevations in serum aminotransferase (transaminase) concentrations. Women who are or may become pregnant and nursing women. Concomitant use with cyclosporine.
Do not use the drug in pregnant and breast-feeding women.
Do not use the drug in patients with liver disease.
If there is myalgia at calf, back or whole body, stop taking drug and consult physician.
Liver function tests should be performed before taking drug and 6 and 12 weeks after taking drug. For patients who routinely use the drug, liver function tests should be performed every 6 months or as recommended by a physician. If the transaminase level is greater than three times of upper normal limit, stop taking drug and consult physician.
Use with caution with digoxin, warfarin because the level of these drug in blood maybe high and became dangerous.
The risk of myopathy/rhabdomyolysis will increase when administer the drug with other following drugs. e.g. azole antifungals such as ketoconazole, itraconazole; macrolides such as erythromycin, clarithromycin; HIV protease inhibitors such as indinavir, ritonavir, nelfinavir, saquinavir; verapamil; diltiazem; gemfibrozil; nicotinic acid; cyclosporine; amiodarone.
The risk of rhabdomyolysis will increase under the following conditions e.g. use at high dose, the elderly; patients with hepatic/renal insufficiency; alcoholism; patients with hypothyroidism.
Use with caution with colchicines, especially in elderly or patients with hepatic/ renal insufficiency because there is risk of myopathy or rhabdomyolysis.
The drug using is possible to increase blood sugar level.
Special Precautions
Sensitivity Reaction: Hypersensitivity reactions, including rash, pruritus, and urticaria have been reported with pitavastatin.
Fetal/Neonatal Morbidity and Mortality: Cholesterol and related compounds are vital for fetal development. Thus, inhibition of cholesterol synthesis is harmful for fetus. Women of child bearing potential should be prevented from pregnancy, by using effective method of contraception, during pitavastatin therapy.
Hepatic Effects: Increased serum aminotransferase concentrations have been reported in patients receiving pitavastatin. These increases usually were mild, transient and resolved or improved with continued or temporary discontinued therapy. Liver function tests should be performed prior to starting of pitavastatin therapy and periodically thereafter, particularly at any increases in pitavastatin dosage. If increases in AST or ALT concentrations exceeding 3 times of the upper limit of normal ranges, dosage of pitavastatin should be reduced or discontinued until the abnormality was resolved. Alcoholic patients should use pitavastatin with special caution and this drug is contraindicated in patients with patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.
Musculoskeletal Effects: There are some reports of myopathy and rhabdomyolysis in patients receiving statins including pitavastatin. These effects can occur at any dosage of statins, but risk increase at higher dose. Predisposing factors of these effects are advanced age, renal impairment, hypothyroidism, and concomitant use of particular antilipemic agents (i.e., fibric acid derivatives and niacin). Patients receiving pitavastatin should be monitored periodically. Pitavastatin therapy should be discontinued if serum creatine kinase (creatine phosphokinase [CK, CPK]) levels markedly increase or myopathy is identified.
Renal Impairment: Dosage adjustments are recommended for patients with creatinine clearance less than 60 mL/min or in patients with end-stage renal disease who are undergoing hemodialysis. Pitavastatin should not be used in severe renal patients (GFR less than 30 mL/min) who are not undergoing hemodialysis. (See Dosage & Administration).
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category X: Pitavastatin is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of pitavastatin in pregnant women, although, congenital abnormalities and/or skeletal malformations have occur in animals.
Lactation: It is not known whether pitavastatin is excreted in human milk, however, it has been shown that a small amount of another drug in this class passes into human milk. Rat studies have shown that pitavastatin is excreted into breast milk. Because another drug in this class passes into human milk and HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, pitavastatin is contraindicated during lactation.
Adverse Reactions
There are 22.2% of patients receiving pitavastatin reported adverse reactions in clinical controlled studies and their open-label extensions exhibited 3.9% of pitavastatin-treated patients were discontinued due to adverse reactions. Adverse reactions reported in this phase include arthralgia, headache, influenza, nasopharyngitis and allergy/hypersensitivity. Laboratory abnormalities are also informed, increase in serum CK, aminotransferase, alkaline phosphatase, bilirubin and glucose.
Postmarketing experience, 2% or more adverse reactions have been identified. Adverse reactions including 3.9% of back pain, 3.1% of myalgia, 3.6% constipation and 2.6% diarrhea observed during postapproval use of pitavastatin. Regardless of causality assessment, adverse reactions reported include the following: abdominal discomfort, abdominal pain, dyspepsia, nausea, asthenia, fatigue, malaise, hepatitis, jaundice, fatal and non-fatal hepatic failure, dizziness, hypoesthesia, insomnia, depression, interstitial lung disease, erectile dysfunction and muscle spasms. The following is clinically significant adverse reactions.
Rhabdomyolysis (unknown incidence): The medical term for the breakdown of muscle fibers that results in the release of muscle fiber contents into the bloodstream. Signs and symptoms considered by pain, tenderness, weakness and swelling of muscles. Besides muscle pain, the other major symptom of rhabdomyolysis is dark, red, or cola colored urine due to myoglobinuria, and serum CK elevation may be observed. The serious complication of rhabdomyolysis, acute renal failure develops and may be associated with high morbidity and mortality, pitavastatin therapy should also be discontinued in any patient with these symptoms.
Myopathy (unknown incidence): The primary symptom is muscle weakness due to dysfunction of muscle fiber, may develop on occasion. Pitavastatin therapy should also be discontinued in any patient with extensive myalgia, muscle tenderness, cramps, stiffness, spasm or noticeable serum CK elevation.
Jaundice, Hepatic Dysfunction (unknown incidence): Persistent significant elevations in hepatic transaminases (AST and ALT) can occur. Check liver enzyme tests before initiating therapy and as routinely. Pitavastatin therapy should also be discontinued if clinically indicated and treat appropriately.
Platelet Count Decreased (unknown incidence): Low platelet levels may detected occasionally. Consequently, close monitoring blood tests are required. If any abnormality is identified, pitavastatin therapy should be discontinued and treat appropriately.
Drug Interactions
Pitavastatin is slightly metabolized by CYP 2C9 and to a lesser extent by CYP 2C8.
Cyclosporine: Co-administration is absolute contraindicated. Pharmacokinetic interaction is reported, 6.6 fold increase of peak plasma concentration (Cmax) and 4.6 fold increase of area under the plasma concentration-time curve (AUC) of pitavastatin. This leads to the risk of serious adverse reaction such as myopathy or rhabdomyolysis.
Fibric acid derivatives (fenofibrate, gemfibrozil, etc.): Pitavastatin should avoid administration concurrently with these medications especially patients with renal problems. Augmented risk of musculoskeletal effects (e.g., myopathy or rhabdomyolysis) and laboratory abnormalities may observed (elevation of CK, blood and urine myoglobin, or aggravation of renal function).
Niacin: Possible increased risk of musculoskeletal effects. Coadministration of pitavastatin and niacin, pitavastatin dosage reduction should be considered.
Erythromycin: Coadministration cause pharmacokinetic interaction, 3.6 fold increase of Cmax and 4.6 fold increase of AUC of pitavastatin. If used concomitantly, the dosage of pitavastatin should not be exceeded 1 mg once daily.
Rifampin: Rifampin significantly increased pitavastatin exposure. In patients taking rifampin, a dose of pitavastatin 2 mg once daily should not be exceeded.
Pitavastatin tablets should be stored in the original package; protect from light at room temperature (not above 30°C).
ATC Classification
C10AA08 - pitavastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
FC tab 2 mg (white, round and embossed with "D.W" on one side and with split line on the other side) x 10 x 10's.
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