Livalo

Livalo

pitavastatin

Manufacturer:

Kowa

Distributor:

Biopharm
Full Prescribing Info
Contents
Pitavastatin calcium.
Description
Livalo tablet contains the following excipients: Lactose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminometasilicate, magnesium stearate, triethyl citrate, hydrated silicon dioxide, titanium oxide, carnauba wax.
Pitavastatin calcium is (+)-monocalcium bis(3R,5S,6E)-7-[2-cyclopropyl- 4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate. It has a molecular formula of C50H46CaF2N2O8 and a molecular weight of 880.98.
It occurs as a white to pale yellowish white powder and is odorless. It is freely soluble in pyridine or in tetrahydrofuran, soluble in ethylene glycol, slightly soluble in methanol, very slightly soluble in ethanol (99.5) or in water, practically insoluble in acetonitrile or in diethyl ether. It dissolves in dilute hydrochloric acid.
Action
Pharmacology: Pitavastatin calcium inhibits HMG-CoA reductase, which is a rate-determining enzyme involved with biosynthesis of cholesterol, in a manner of competition with the substrate so that it inhibits cholesterol synthesis in the liver. As a result, the expression of LDL-receptors followed by the uptake of LDL from blood to liver is accelerated and then the plasma total cholesterol decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases VLDL secretion into blood, thus plasma triglyceride levels decrease.
Inhibition of HMG-CoA Reductase: Pitavastatin calcium antagonistically inhibited HMG-CoA reductase in a study by using rat hepatic microsomes, the IC50 was 6.8 nM (in vitro).
Inhibition of Cholesterol Synthesis: Pitavastatin calcium inhibited cholesterol synthesis dose-dependently in a study by using human liver cancer derived cells (HepG2) (in vitro). Moreover, liver-selective inhibition of cholesterol synthesis in case of oral administration was observed (rats).
Plasma Lipid Lowering Effect: Plasma total cholesterol and plasma triglycerides were significantly decreased by oral administration of pitavastatin calcium (dogs, guinea pigs).
Suppressing Effects on Lipid Accumulation and Intimal Thickening: Pitavastatin calcium suppressed the accumulation of cholesteryl ester in macrophages loaded by oxidized-LDL (murine monocyte derived cell line) in vitro. Further, it significantly suppressed the intimal thickening in a model rabbit with a balloon-injured carotid artery through oral administration (rabbit).
Mechanism of Action: Acceleration of LDL-Receptor Expression: Pitavastatin calcium accelerated the expression of mRNA for LDL-receptor in HepG2 cells so that the binding and the uptake of LDL and the apoB-degradation were increased (in vitro). Moreover, it accelerated LDL-receptor expression dose-dependently by oral administration (guinea pigs).
VLDL-Secretion Lowering Effect: The secretion of VLDL-triglyceride was significantly decreased by the oral administration of pitavastatin calcium (guinea pigs).
Pharmacokinetics: Pharmacokinetics in Adult Male Human Subjects: Plasma concentration after single dose oral administration: In 6 healthy adult male humans, single dose oral administration of pitavastatin calcium (2 mg or 4 mg) was performed under fasted conditions. Unchanged pitavastatin and its lactone, the main metabolite, were mainly found in plasma. The pharmacokinetic parameters after the administration of pitavastatin calcium (2 mg) is shown in the table as follows.
Effect of Food: Single oral dose administration demonstrated a delay in Tmax and a decrease in Cmax, but no significant difference in AUC (see Table 1).

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Blood Concentration After Repeated Oral Administration: After repeated oral administration of pitavastatin calcium 4 mg once a day, after breakfast for 7 days in 6 healthy adult human males, fluctuation of the pharmacokinetic parameters by repeated administration was slight and T½ was around 11 hrs. (See Table 2.)

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Furthermore, after a 5-day repeated oral administration of pitavastatin calcium 2 mg once a day in 6 elderly subjects and 5 non-elderly subjects, no significant difference in the pharmacokinetic parameters in either cohort was observed.
Blood Concentration by Co-administration with Cyclosporin: Six-day repeated oral administration of pitavastatin calcium 2 mg in 6 healthy adult male subjects was performed with the administration of cyclosporin 2 mg/kg 1 hr before the administration of pitavastatin calcium on day 6. The plasma concentration of the unchanged pitavastatin increased by 6.6 times based on Cmax and by 4.6 times based on AUC compared to the control value.
Plasma Concentration by Co-administration with Fibrates (Data from Foreign Subjects): In 24 healthy adult humans, 6-day repeated oral administration of pitavastatin calcium 4 mg was performed followed by 1-day washout and then 7-day repeated oral co-administration of pitavastatin calcium 4 mg and fenofibrate or gemfibrozil. The plasma concentrations on the unchanged pitavastatin (AUC) increased by 1.2 times in fenofibrate and 1.4 times in gemfibrozil.
Pharmacokinetics in Hepatic Dysfunction: Cirrhosis (Data from Foreign Subjects): Single oral administration of pitavastatin calcium 2 mg in 12 patients with cirrhosis and 6 healthy volunteers was performed. The plasma concentration in the patients classified as Child-Pugh class A increased by 1.3 times based on Cmax and by 1.6 times based on AUC compared with normal hepatic function and that in Child-Pugh class B increased by 2.7 times based on Cmax and by 3.9 times based on AUC.
Fatty Liver Disease: Seven-day repeated oral administration of pitavastatin calcium 2 mg was performed in 6 patients with fatty liver and 6 subjects with normal hepatic function. The effect on the pharmacokinetics was minimal.
Urinary Excretion: After single oral administration of pitavastatin calcium 2 mg or 4 mg in 6 healthy adult male humans, the urinary excretion rate of the unchanged pitavastatin was <0.6%, and that of its lactone metabolite was <1.3%. The total excretion rate of the unchanged pitavastatin and its lactone was <2% of the dose.
After 7-day repeated oral dose of pitavastatin 4 mg once a day in 6 healthy adult human males, the urinary excretion of the unchanged pitavastatin and its lactone metabolite showed no increase during the period from the first administration until day 7 and decreased rapidly after completion of administration.
Metabolism: Pitavastatin calcium was metabolized by cyclization to its lactone, β-oxidation on the side-chain, hydroxylation of the quinoline ring and glucuronate or taurine conjugation. The main route of excretion was rectally (rats, dogs).
In humans, the unchanged pitavastatin and its lactone metabolite as the main metabolite were mainly observed in blood and the other metabolites eg, propionate derivative and 8-hydroxide were minimally observed. Meanwhile, the unchanged pitavastatin, its lactone, dehydro-lactone, 8-hydroxide and these conjugates were minimally observed in urine.
Drug-Metabolizing Enzymes: Pitavastatin calcium was minimally metabolized in study using human hepatic microsomes and the 8-hydroxide occurred mainly by CYP2C9 metabolism (in vitro).
An inhibitory study against model substrate of CYP species demonstrated that pitavastatin calcium did not affect the metabolism of tolbutamide, a substrate for CYP2C9 and testosterone, a substrate for CYP3A4 (in vitro).
Plasma Protein Binding Rate: Plasma protein binding rate of pitavastatin calcium was as high as 99.5-99.6% with 4% human serum albumin and 94.3-94.9% with 0.06% human α1-acid glycoprotein (in vitro).
Clinical Studies: The aggregated result of clinical studies (including a double-blind comparative study) by the administration of pitavastatin (1-4 mg) once a day for 8-104 weeks in 862 patients with hypercholesterolemia including familial hypercholesterolemia, showed a significant effect on serum lipids improvement. On week 8, the decline of total cholesterol was 28%, that of LDL-cholesterol was 40%, and that of triglyceride was 26% in patients with triglyceride levels ≥150 mg/dL before the administration. No difference between the elderly and the non-elderly subjects in the decline of total cholesterol was observed.
Furthermore, a long-term administration study (28-52 weeks) in patients with hypercholesterolemia indicated sustained and stable serum lipids improvement. Moreover, stable decrease in total cholesterol value and that of LDL-cholesterol value were observed on the long-term administration study (52-104 weeks) in patients with familial hypercholesterolemia.
Livalo has not been proven to prevent the associated complications of lipid abnormalities eg, coronary heart disease as mortality and morbidity studies with Livalo have not yet been completed.
Effect on Blood Steroid Hormones in the Elderly: Oral administration of pitavastatin calcium 2 mg once a day for 8 weeks in 34 hyperlipidemic patients ≥70 years indicated no significant change on the blood steroid hormones.
Effect on Sugar Metabolism in Hyperlipidemic Patients with Concomitant Diabetes: Oral administration of pitavastatin calcium 2 mg once a day for 8 weeks in 33 hyperlipidemic patients with concomitant non-insulin dependent diabetes affected a little on the blood sugar control.
Indications/Uses
Hypercholesterolemia, familial hypercholesterolemia.
Dosage/Direction for Use
Adults: Usual Dose: 1-2 mg 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.
Hepatic Impairment: Initially 1 mg/day, maximum of 2 mg/day.
Contraindications
Patients with a history of hypersensitivity to any of the components of Livalo.
Patients with severe hepatic disorders or biliary atresia (in these patients, plasma concentration of Livalo rises, and the frequency of development of adverse reactions may increase. In addition, hepatic disorders may be aggravated) (see Pharmacokinetics under Actions).
Patients receiving cyclosporine (plasma concentration of this product rises, and the frequency of development of adverse reactions may increase. In addition, severe adverse reactions eg, rhabdomyolysis may occur) (see Interactions and Pharmacokinetics under Actions).
Pregnant women, women suspected of being pregnant, or lactating women.
For patients with abnormal clinical laboratory values related to renal function, co-administration with fibrate agents should not be allowed except when that co-administration is considered indispensable (Rhabdomyolysis is more likely to occur) (see Interactions).
Special Precautions
Administration of Livalo 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 cases of familial hypercholesterolemia, administration of this drug should be considered as a treatment supplementary to non-drug therapy eg, LDL-apheresis only when treatment with Livalo is judged indispensable.
In the case of an increase in dosage of Livalo, rhabdomyolysis-related adverse events may occur. When the dosage is increased to 4 mg, some attention should be given to early signs of rhabdomyolysis eg, CK (CPK) elevation, myoglobinuria, myalgia and weakness. (In overseas clinical studies, doses of ≥8 mg were discontinued due to several cases of rhabdomyolysis and related adverse events.)
Livalo should be administered carefully in the following patients:
Patients with Hepatic Disorders or History of Hepatic Disease or Alcoholic Patients: Because Livalo is primarily distributed and acts in the liver, hepatic disorders may be aggravated. Furthermore, it has been reported that rhabdomyolysis is more likely to occur in alcoholic patients.
Patients with Renal Disorder or History of Renal Disorder: It has been reported that many of the patients who had rhabdomyolysis also had renal dysfunction. Cases of acute aggravation of renal function accompanying rhabdomyolysis were also reported.
Patients who are receiving fibrate agents (eg, bezafibrate) and niacin (rhabdomyolysis is more likely to occur) (see Interactions).
Patients with hypothyroidism, hereditary muscle disorders (eg, muscular dystrophy) or a family history of these, a history of drug-induced myopathy (it has been reported that rhabdomyolysis is more likely to occur).
Important Essential Precautions: When using Livalo, dietary advice should be given first, consider further exercise therapy and reduce the risk factors of ischemic heart disease eg, hypertension/smoking.
Liver function tests should be performed once or more during the first 12 weeks of therapy, and thereafter, periodically (once every 6 months, or more frequently).
The plasma lipid levels should be regularly tested during administration of Livalo. When the patient does not respond to therapy, administration of Livalo should be discontinued.
Other Precautions: In an oral administration study in dogs (≥3 mg/kg/day for 3 months, ≥1 mg/kg/day for 12 months), the development of cataracts was found. However, no cataract was found in other animals (rats, monkeys).
Use in Pregnancy & Lactation: Livalo should not be administered to pregnant women or women who may be pregnant. The safety of Livalo in pregnant women has not been established. In the animal study in rats, administration in the perinatal and lactation periods (≥1 mg/kg) resulted in death of dams before or after childbirth in a certain perinatal stage. In an organogenesis period administration study in rabbits (≥0.3 mg/kg), death of dams was found. Fetal skeletal anomalies were found when a large dose of HMG-CoA reductase inhibitor was administered to rats. In humans, occurrence of congenital anomalies of the fetus was reported when a HMG-CoA reductase inhibitor was administered up to 3 months during pregnancy.
Livalo should not be administered to lactating women. Animal studies (rats) have shown that this product is excreted in breast milk.
Use in Children: The safety of Livalo in children has not been established (no clinical experience).
Use in the Elderly: Since elderly patients generally have reduced physiological function, careful supervision and measures eg, reducing the dose is recommended. It has been reported that rhabdomyolysis is more likely to occur in the elderly.
Use In Pregnancy & Lactation
Livalo should not be administered to pregnant women or women who may be pregnant. The safety of Livalo in pregnant women has not been established. In the animal study in rats, administration in the perinatal and lactation periods (≥1 mg/kg) resulted in death of dams before or after childbirth in a certain perinatal stage. In an organogenesis period administration study in rabbits (≥0.3 mg/kg), death of dams was found. Fetal skeletal anomalies were found when a large dose of HMG-CoA reductase inhibitor was administered to rats. In humans, occurrence of congenital anomalies of the fetus was reported when a HMG-CoA reductase inhibitor was administered up to 3 months during pregnancy.
Livalo should not be administered to lactating women. Animal studies (rats) have shown that this product is excreted in breast milk.
Adverse Reactions
In the clinical studies conducted by the time of approval, adverse reactions were found in 197 patients (22.2%) out of 886 patients. Adverse reactions in subjective and objective symptoms were seen in 50 patients (5.6%). The main symptoms were abdominal pain, rash, malaise, numbness and pruritus. Adverse reactions pertaining to clinical laboratory values were found in 167 patients (18.8%) and the main changes were elevations of γ-GTP, CK (CPK), serum ALT (GPT) and serum AST (GOT).
Clinically Significant Adverse Reactions: Rhabdomyolysis (frequency unknown): Rhabdomyolysis characterized by myalgia, weakness, CK (CPK) elevation, elevated blood and urinary myoglobin may develop. Since serious renal disorders eg, acute renal failure may develop occasionally in association with rhabdomyolysis, administration of Livalo should be discontinued if such symptoms are noted.
Myopathy (frequency unknown): Myopathy may develop occasionally. Therefore, when extensive myalgia, muscular tenderness or marked CK (CPK) elevation is noted, administration of Livalo should be discontinued.
Hepatic Dysfunction, Jaundice (frequency unknown): Hepatic dysfunction and/or jaundice with significant elevation of AST (GOT) and ALT (GPT) may develop. Regular observations eg, liver function tests are required. If any abnormality is observed, discontinue the administration and treat appropriately.
Decrease Platelet Count (frequency unknown): Decrease platelet count may develop occasionally. Therefore, close observations eg, blood tests are required. If any abnormality is observed, discontinue the administration and treat appropriately.
Other Adverse Reactions: See Table 3.

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Drug Interactions
Livalo is minimally metabolized by hepatic cytochrome P-450 isozymes (slightly metabolized by CYP2C9).
Absolute Contraindications for Co-administration: Cyclosporin: Serious adverse events eg, rhabdomyolysis accompanied by deterioration of renal function are more likely to occur. Plasma concentration of Livalo is elevated by cyclosporin (Cmax by 6.6 times and AUC by 4.6 times).
Relative Contraindications for Co-administration: As a general rule, Livalo should not be co-administered with the following drugs to patients with abnormal clinical laboratory values related to renal function. Livalo should be carefully co-administered when co-administration is considered indispensable for the treatment.
Fibrates, Bezafibrates, etc: Rhabdomyolysis accompanied by sudden aggravation of renal function is more likely to occur. If subjective symptoms (myalgia, weakness) develop, elevations of CK (CPK), blood and urinary myoglobin or aggravation of renal function eg, elevation of serum creatinine is noted, administration of Livalo should be discontinued immediately.
Precautions for Co-administration: See Table 4.

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Caution For Usage
When dispensing Livalo: For drugs that are dispensed in a press through package (PTP), remove Livalo from the package prior to administration. It has been reported that if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications eg, mediastinitis.
Storage
Store at room temperature (below 25°C). Protect from light.
ATC Classification
C10AA08 - pitavastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
FC tab (white) 2 mg x 100's.
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