(pit a'' va stat' in)
|Content & Description||
Pitavastatin tablet contains the following excipients: Lactose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminometasilicate, magnesium stearate, triethyl citrate, hydrated silicon dioxide, titanium oxide, carnauba wax.
|Indications||Hypercholesterolemia, familial hypercholesterolemia.|
|Dosage & Administration||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 Pitavastatin.
Patients with severe hepatic disorders or biliary atresia (in these patients, plasma concentration of Pitavastatin 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 Pitavastatin 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 Pitavastatin is judged indispensable.
In the case of an increase in dosage of Pitavastatin, 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 â‰¥8 mg were discontinued due to several cases of rhabdomyolysis and related adverse events.)
Pitavastatin should be administered carefully in the following patients:
Patients with Hepatic Disorders or History of Hepatic Disease or Alcoholic Patients: Because Pitavastatin 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 Pitavastatin, 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 Pitavastatin. When the patient does not respond to therapy, administration of Pitavastatin should be discontinued.
Other Precautions: In an oral administration study in dogs (â‰¥3 mg/kg/day for 3 months, â‰¥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: Pitavastatin should not be administered to pregnant women or women who may be pregnant. The safety of Pitavastatin in pregnant women has not been established. In the animal study in rats, administration in the perinatal and lactation periods (â‰¥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 (â‰¥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.
Pitavastatin 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 Pitavastatin 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.
|Adverse Drug 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 Î³-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 Pitavastatin 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 Pitavastatin 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.
|Drug Interactions||Pitavastatin 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 Pitavastatin is elevated by cyclosporin (Cmax by 6.6 times and AUC by 4.6 times).
Relative Contraindications for Co-administration: As a general rule, Pitavastatin should not be co-administered with the following drugs to patients with abnormal clinical laboratory values related to renal function. Pitavastatin 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 Pitavastatin should be discontinued immediately.
|Pregnancy Category (US FDA)||Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.|
|Caution For Usage||When dispensing Pitavastatin: For drugs that are dispensed in a press through package (PTP), remove Pitavastatin 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.|
|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 Tmaxand a decrease in Cmax, but no significant difference in AUC.
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.
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, Î²-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 Î±1-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 â‰¥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.
Pitavastatin has not been proven to prevent the associated complications of lipid abnormalities eg, coronary heart disease as mortality and morbidity studies with Pitavastatin 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 â‰¥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.
|ATC Classification||C10AA08 - pitavastatin; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.|
|Brand Name||Manufacturer/Marketer||Composition||Dosage Form||Pack Size & Price|
|PITAVAS||Aristopharma Ltd.||Pitavastatin calcium INN 2mg||Film Coated Tablet||30's: 300.00 MRP|
|PIVALO 2||Square Pharmaceuticals Ltd.||Pitavastatin 2mg||Tablet||3x10's: 300.90 MRP|
|PIVALO 4||Square Pharmaceuticals Ltd.||Pitavastatin 4mg||Tablet||2x10's: 361.00 MRP|
Why is this medication prescribed?
Pitavastatin is used together with diet, weight-loss, exercise to reduce the amount of fatty substances such as low-density lipoprotein (LDL) cholesterol ('bad cholesterol') in the blood and to increase the amount of high-density lipoprotein (HDL) cholesterol ('good cholesterol'). Pitavastatin is in a class of medications called HMG-CoA reductase inhibitors (statins). It works by slowing the production of cholesterol in the body to decrease the amount of cholesterol that may build up on the walls of the arteries and block blood flow to the heart, brain, and other parts of the body.
How should this medicine be used?
Pitavastatin comes as a tablet to take by mouth. It is usually taken once a day with or without food. Take pitavastatin at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor to explain any part you do not understand. Take pitavastatin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Your doctor may start you on a low dose of pitavastatin and gradually increase your dose, not more than once every 4 weeks.
Continue to take pitavastatin even if you feel well. Do not stop taking pitavastatin without talking to your doctor.
Other uses for this medicine
- tell your doctor if you are allergic to pitavastatin, any other medications, or any of the ingredients in pitavastatin tablets.
- tell your doctor if you are taking cyclosporine (Gengraf, Neoral, Sandimmune). Your doctor will probably tell you not to take pitavastatin if you are taking this medication.
- tell your doctor what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: erythromycin other cholesterol-lowering medications such as fenofibrate, gemfibrozil, and niacin; rifampin; ritonavir taken with atazanavir or darunavir; ritonavir and lopinavir or warfarin. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you have liver disease. Your doctor will order laboratory tests to see how well your liver is working even if you do not think you have liver disease. Your doctor will probably tell you not to take pitavastatin if you have liver disease or if the tests show that you may be developing liver disease.
- tell your doctor if you drink large amounts of alcohol, if you have ever had liver disease, or if you have or have ever had seizures, low blood pressure, or thyroid or kidney disease.
- tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are taking pitavastatin. Talk to your doctor about birth control methods that will work for you. If you become pregnant while taking pitavastatin, stop taking pitavastatin and call your doctor immediately. Pitavastatin may harm the fetus.
- do not breast-feed while you are taking this medication.
you should know that the risk that you will develop serious muscle problems during your treatment is higher if you are 65 years of age or older. Talk to your doctor about the risks of taking pitavastatin.
- if you are having surgery, tell the doctor that you are taking pitavastatin. If you are hospitalized due to serious injury or infection, tell the doctor treating you that you are taking pitavastatin.
- ask your doctor about the safe use of alcoholic beverages while you are taking pitavastatin. Alcohol can increase the risk of serious side effects.
What special dietary instructions should I follow?
Eat a low-fat, low-cholesterol diet. Be sure to follow all exercise and dietary recommendations made by your doctor or dietitian. You can also visit the U.S. National Cholesterol Education Program (NCEP) website for additional dietary information at http://www.nhlbi.nih.gov/health/public/heart/chol/chol_tlc.pdf.
What should I do if I forget a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?
Pitavastatin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
memory loss or forgetfulness
Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical help:
muscle pain, tenderness, or weakness
unusual bleeding or bruising
lack of energy
loss of appetite
pain in the upper right part of the stomach
yellowing of the skin or eyes
Pitavastatin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.
What should I know about storage and disposal of this medication?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.
In case of emergency/overdose
In case of overdose, consult your doctor. If the victim has collapsed or is not breathing, consult local medical emergency services.
What other information should I know?
Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to this medicine.
Do not let anyone else use your medication. If you still have symptoms and need further treatment, consult your doctor.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
Ref: U.S. National Library of Medicine.
This information is provided for reference only and not a replacement for and should only be used in conjunction with full consultation with a registered medical practitioner. It may not contain all the available information you require and cannot substitute professional medical care, nor does it take into account all individual circumstances. Although great effort has been made to ensure content accuracy, mph-bd shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise.