Livalo

Pitavastatin calcium.

Each tablet contains 2.0 mg of pitavastatin calcium.
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 odorless powder. 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.
Excipients/Inactive Ingredients: Lactose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminometasilicate, magnesium stearate, triethyl citrate, hydrated silicon dioxide, titanium oxide, carnauba wax, food yellow No. 5 (sunset yellow FCF).

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. Furthermore, 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 after the oral administration of pitavastatin calcium 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. Furthermore, it significantly suppressed the intimal thickening with a balloon-injured carotid artery through oral administration (rabbits).
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).
Clinical Studies: The aggregated result of clinical studies (including a double-blind comparative study) by the administration of pitavastatin calcium (1 to 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 was observed between the elderly and the non-elderly subjects in the reduction of total cholesterol.
Furthermore, a long-term administration study (28 to 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 to 104 weeks) in patients with familial hypercholesterolemia.
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 aged 70 years old or older 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.
Pharmacokinetics: Pharmacokinetics in Adult Male Human Subjects: Plasma concentration after single dose oral administration: In 6 healthy adult male human subjects, 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) are shown in the following table.
Effect of food on pharmacokinetics of unchanged pitavastatin: single oral dose administration demonstrated a delay in T_max and decrease in C_max, but no significant difference in AUC. (See Table 1 and Figure.)

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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 male subjects, fluctuation of the pharmacokinetic parameters by repeated administration was slight, and T_½ was around 11 hours. (See Table 2.)

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Furthermore, after 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.
Pharmacokinetics in Patients with Hepatic Dysfunction: Cirrhosis (Data from foreign subjects): Single oral administration of pitavastatin calcium (2 mg) in 12 patients with cirrhosis and 6 healthy adult human subjects was performed. The plasma concentration in the patients classified as Child-Pugh grade A increased by 1.3 times based on C_max and by 1.6 times based on AUC compared with normal hepatic function, and, that in patients classified as Child-Pugh grade B increased by 2.7 times based on C_max 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.
Pharmacokinetics in Patients with Renal Dysfunction: Single oral administration of pitavastatin calcium (2 mg) for 7 days in 6 patients with renal dysfunction (serum creatinine ≥1.5 x normal upper limit, to ≤ 3 x normal upper limit) and hypercholesterolemia and 6 patients with normal renal function and hypercholesterolemia was performed. The plasma concentration in the patients with renal dysfunction and hypercholesterolemia increased by 1.7 times based on C_max and by 1.9 times based on AUC compared with patients with normal renal function and hypercholesterolemia.
Drug-drug Interaction: In vitro studies: *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. It was demonstrated that an organic anion transporting polypeptide, OATP1B1 (OATP-C/OATP2) is involved in the uptake of pitavastatin into liver, and the uptake of pitavastatin into liver was inhibited by cyclosporine, erythromycin or rifampicin.
Clinical studies: Cyclosporine: Six-day repeated oral administration of pitavastatin calcium (2 mg) in 6 healthy adult male subjects was performed with the administration of cyclosporine (2 mg/kg) 1 hour before the administration of pitavastatin calcium on day 6. The plasma concentration of the unchanged pitavastatin increased by 6.6 times based on C_max and by 4.6 times based on AUC compared with the control value.
Erythromycin (Data from foreign subjects): In 18 healthy adult human subjects, 6-day repeated oral administration of erythromycin (500 mg) four times daily was performed accompanied with a single administration of pitavastatin calcium 4 mg on day 4. As the results, the plasma concentration of pitavastatin increased by 3.6 times based on C_max and by 2.8 times based on AUC compared with pitavastatin alone.
Rifampicin (Data from foreign subjects): In 18 healthy adult human subjects, 15-day repeated oral administration of rifampicin (600 mg) was performed accompanied with 5-day repeated oral administration of pitavastatin calcium (4 mg) once daily on day 11-15. As the results, the plasma concentration of pitavastatin increased by 2.0 times based on C_max and by 1.3 times based on AUC compared with pitavastatin alone.
Plasma concentration by co-administration with fibrates (Data from foreign subjects): In 24 healthy adult human subjects, 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 of the unchanged pitavastatin (AUC) increased by 1.2 times in case of fenofibrate and 1.4 times in case of gemfibrozil.
Warfarin (Data from foreign subjects): In 23 healthy adult male subjects, 21-day repeated oral administration of warfarin (individually titrated dose) on day 1-21 was performed accompanied with 9-day repeated oral administration of pitavastatin calcium (4 mg) once daily on day 14-22. As the results, the plasma concentration of R-warfarin increased by 1.034 times based on C_max and by 1.066 times based on AUC, the plasma concentration of S-warfarin increased by 1.033 times based on C_max and by 1.058 times based on AUC compared with warfarin alone. Pitavastatin calcium had no significant pharmacokinetic interaction with R- and S- warfarin. The steady-state pharmacodynamics (prothrombin time [PT] and international normalized ratio [INR]) of warfarin in healthy subject were unaffected by the co-administration of pitavastatin 4 mg daily. However, patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to their therapy.
Darunavir/Ritonavir (Data from foreign subjects): In 27 healthy adult human subjects, pitavastatin 4 mg was administered once daily (days 1-5 and days 12-16), darunavir/ritonavir 800mg/100mg was administered (days 6-16). As the results, the plasma concentration of pitavastatin decreased by 0.96 times based on C_max and by 0.74 times based on AUC compared with pitavastatin alone.
Lopinavir/Ritonavir (Data from foreign subjects): In 23 healthy adult human subjects, pitavastatin 4 mg was administered once daily (days 1-5 and days 20-24), lopinavir/ritonavir 400mg/100mg was administered (days 9-24). As the results, the plasma concentration of pitavastatin decreased by 0.99 (58.2/58.6) times based on C_max and by 0.83 (113.9/136.8) times based on AUC compared with pitavastatin alone. The effect on exposures when pitavastatin and lopinavir/ritonavir are coadministered was minimal. Concomitant use of pitavastatin and lopinavir/ritonavir was safe and well tolerated.
Atazanavir (Data from foreign subjects): In 17 healthy adult human subjects, 9-day repeated oral administration of atazanavir (300 mg) was performed accompanied with 5-day repeated oral administration of pitavastatin calcium (4 mg) once daily on day 5-9. As the results, the plasma concentration of pitavastatin increased by 1.6 times based on C_max and by 1.3 times based on AUC compared with pitavastatin alone. When atazanavir is co-administered with pitavastatin there is a small increase in maximum concentrations of and exposure to both pitavastatin and atazanavir compared to when they are administered alone. In this study these changes in pharmacokinetics did not appear to affect any safety parameters measured.
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 less than 0.6%, and that of its lactone metabolite was less than 1.3%. The total excretion rate of the unchanged pitavastatin and its lactone was less than 2% of the dose.
After 7-day repeated oral dose of pitavastatin (4 mg) once a day in 6 healthy adult male human subjects, 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 human subjects, the unchanged pitavastatin and its lactone metabolite as the main metabolite were mainly observed in blood, and the other metabolites such as 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 its 8-hydroxide occurred mainly by CYP2C9 metabolism (in vitro).
Plasma Protein Binding Rate: Plasma protein binding rate of pitavastatin calcium was as high as 99.5% to 99.6% with human plasma or 4% human serum albumin and 94.3% to 94.9% with 0.06% human α₁-acid glycoprotein (in vitro).

Hypercholesterolemia, Familial hypercholesterolemia and Mixed Dyslipidemia.
To reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) and Apo A1 who response to diet and other measures is inadequate.

Pitavastatin calcium can be taken with or without food, at any time of day. It is desirable to take the tablet at the same time each day.
Dose Range: 1 mg to 4 mg once daily.
Primary hyperlipidemia and mixed dyslipidemia: Starting dose 2 mg. When lowering of LDL-C is insufficient, the dosage may be increased to a maximum of 4 mg per day.

There is no specific treatment in the event of overdose. The patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK Levels should be monitored. Haemodialysis is unlikely to be of benefit.

(Don't administer to the following patients): Patients with a history of hypersensitivity to any of the components of this product.
Patients with severe hepatic disorders or biliary atresia [In these patients, plasma concentration of this product rises, and the frequency of the occurrence of adverse reactions may increase. In addition, hepatic disorders may be aggravated]. (See Pharmacology: Pharmacokinetics under Actions.)
Patients receiving cyclosporine [Plasma concentration of this product rises, and the frequency of the occurrence of adverse reactions may increase. In addition, severe adverse reactions such as rhabdomyolysis may occur]. (See Interactions and Pharmacology: Pharmacokinetics under Actions.)
Pregnant women, women suspected of being pregnant, or lactating women (see Use in Pregnancy & Lactation).
Relative Contraindications (As a general rule, the co-administration of this product is contraindicated in the following situation. If the use of this product is considered essential, it should be administered carefully): For patients with abnormal clinical laboratory values related to renal function, co-administration with fibrates should not be undertaken except when that co-administration is considered essential. [Rhabdomyolysis is more likely to occur.] (See Interactions.)

Precautions related to indications: Administration of this drug should be considered only 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 such as LDL-apheresis only when treatment with this drug is judged indispensable.
Precautions related to dosage and administration: In the case of administration to patients with hepatic dysfunction, the starting dose should be 1 mg per day and the maximum dose should be 2 mg per day. [See Careful Administration as follows and Pharmacology: Pharmacokinetics under Actions.]
As the dose of this drug is increased, rhabdomyolysis-related adverse events may occur. When the dose is increased to 4 mg, attention should be given to the 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.)
Careful Administration (This product should be administered carefully to the following patients): Patients with hepatic dysfunction or alcoholism [Because this product is primarily distributed and acts in the liver, hepatic dysfunction may be aggravated. Furthermore, it has been reported that rhabdomyolysis is more likely to occur in alcoholic patients].
Patients with renal dysfunction or a history of renal dysfunction [It has been reported that many of the patients who had rhabdomyolysis also had renal dysfunction. Cases of acute aggravation deterioration of renal function accompanying rhabdomyolysis were also reported].
Patients who are receiving fibrates (such as bezafibrate) and niacin [Rhabdomyolysis is more likely to occur]. (See Interactions.)
Patients with hypothyroidism, hereditary muscular disorders (such as 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 General Precautions: When using this product, the followings should be carefully noted: Dietary advice should be given first, and then consider further exercise therapy and reduce the risk factors of ischemic heart disease such as hypertension and smoking.
Liver function tests should be performed once or more during the first 12 weeks of administration, and thereafter, periodically (once every 6 months, or more frequently).
The plasma lipid levels should be regularly tested during administration of this product. When the patient does not respond to therapy, administration of this drug should be discontinued.
Other precautions: It has been reported that there were immune-mediated necrotising myopathy characterised by proximal muscle weakness, elevated serum creatine kinase and necrotising myopathy without inflammation that persist despite discontinuation of statin treatment and improve with immunosuppressive agents.
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 observed. However, no cataract was observed in other animals (rats, monkeys).
Use in Children: The safety of this drug 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 such as reducing the dose is recommended. [It has been reported that rhabdomyolysis is more likely to occur in the elderly.]

This product should not be administered to pregnant women or women who may be pregnant. [The safety of this product in pregnant women has not been established. In an animal study in rats, administration in the perinatal and lactation periods (1 mg/kg and above) 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 and above), death of dams was observed. Fetal skeletal anomalies were found when a large dose of an HMG-CoA reductase inhibitor was administered to rats. In humans, occurrence of congenital anomalies of the fetus was reported when an HMG-CoA reductase inhibitor was administered up to 3 months during pregnancy.]
This product should not be administered to lactating women. [Animal studies (rats) have shown that this product is excreted in breast milk.]

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) (at the approval).
In a drug use investigation on the drug use results, adverse reactions were found in 1,210 patients (6.0%) out of 20,002 patients (at the time of 5^th periodic safety report).
Clinically significant adverse reactions: Rhabdomyolysis (frequency unknown): Rhabdomyolysis characterized by myalgia, weakness, CK (CPK) increased, blood and urinary myoglobin increased may occur. Since serious renal disorders such as acute renal failure may occur in association with rhabdomyolysis, administration of this product should be discontinued if such symptoms are observed.
Myopathy (frequency unknown): Myopathy may occur. Therefore, when extensive myalgia, muscular tenderness or marked CK (CPK) increased is observed, administration of this product should be discontinued.
Hepatic dysfunction, Jaundice (less than 0.1%): Hepatic dysfunction and/or jaundice with significant AST (GOT) and ALT (GPT) increased may occur. Regular observations such as liver function tests are required. If any abnormality is observed, discontinue the administration of this product and treat with the appropriate therapy.
Platelet count decreased (frequency unknown): Platelet count decreased may develop occasionally. Therefore, close observations such as blood tests are required. If any abnormality is observed, discontinue the administration of this product and treat with the appropriate therapy.
Interstitial pneumonia (less than 0.1%): Interstitial pneumonia may occur. Therefore, even in long-term administration, if any abnormalities such as fever, coughing, dyspnoea or relevant chest X-ray test findings are observed, discontinue the administration of this product and treat with appropriate therapies such as the administration of adrenal corticosteroid.
Other adverse reactions: See Table 3.

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This product is minimally metabolized by hepatic cytochrome P-450 isozymes. (It is slightly metabolized by CYP2C9.)
Absolute contraindications for co-administration: See Table 4.

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Relative contraindications for co-administration: As a general rule, this product should not be co-administered with the following drugs to the patients with abnormal clinical laboratory values related to renal function. This product should be carefully co-administered when co-administration is considered indispensable for the treatment. (See Table 5.)

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Precautions for co-administration: See Table 6.

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When dispensing the drug: For drugs that are dispensed in a press through package (PTP), instruct the patient to remove the drug from PTP sheet prior to taking. [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 such as mediastinitis.]

Protect from light and do not store above 30°C.

Dyslipidaemic Agents

C10AA08 - pitavastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

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