Pitator

Pitator

pitavastatin

Manufacturer:

Orient Pharma

Distributor:

Zuellig

Marketer:

OEP Phils
Full Prescribing Info
Contents
Pitavastatin calcium.
Description
Each film-coated tablet contains Pitavastatin Calcium 2 mg.
Action
Pharmacology: Mechanism of Action: Pitavastatin competitively 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 TC decreases. Further, the sustained inhibition of cholesterol synthesis in the liver decreases levels of very low density lipoproteins.
Pharmacodynamics: The magnitude of LDL-C reduction by pitavastatin (2 mg and 4 mg) is comparable to atorvastatin (10 mg and 20 mg) and simvastatin (20 mg and 40 mg). It also does not prolong the QTc interval to a clinically significant degree.
Pharmacokinetics: Absorption: Pitavastatin peak plasma concentrations are achieved about 1 hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single Pitavastatin doses from 1 to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%. Administration of Pitavastatin with a high fat meal (50% fat content) decreases pitavastatin Cmax by 43% but does not significantly reduce pitavastatin AUC. The Cmax and AUC of pitavastatin did not differ following evening or morning drug administration. In healthy volunteers receiving 4 mg pitavastatin, the percent change from baseline for LDL-C following evening dosing was slightly greater than that following morning dosing. Pitavastatin was absorbed in the small intestine but very little in the colon.
Distribution: Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and α1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. Association of pitavastatin and/or its metabolites with the blood cells is minimal.
Metabolism: Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7).
Excretion: A mean of 15% of radioactivity of orally administered, single 32 mg 14C-labeled pitavastatin dose was excreted in urine, whereas a mean of 79% of the dose was excreted in feces within 7 days. The mean plasma elimination half-life is approximately 12 hours.
Race: In pharmacokinetic studies, pitavastatin Cmax and AUC were 21 and 5% lower, respectively in Black or African American healthy volunteers compared with those of Caucasian healthy volunteers. In pharmacokinetic comparison between Caucasian volunteers and Japanese volunteers, there were no significant differences in Cmax and AUC.
Gender: In a pharmacokinetic study which compared healthy male and female volunteers, pitavastatin Cmax and AUC were 60 and 54% higher, respectively in females. This had no effect on the efficacy or safety of Pitavastatin in women in clinical studies.
Geriatric: In a pharmacokinetic study which compared healthy young and elderly (≥ 65 years) volunteers, pitavastatin Cmax and AUC were 10 and 30% higher, respectively, in the elderly. This had no effect on the efficacy or safety of Pitavastatin in elderly subjects in clinical studies.
Renal Impairment: In patients with moderate renal impairment (glomerular filtration rate of 30-59 mL/min/1.73 m2) and end stage renal disease receiving hemodialysis, pitavastatin AUC0-inf is 102 and 86% higher than those of healthy volunteers, respectively, while pitavastatin Cmax is 60 and 40% higher than those of healthy volunteers, respectively. Patients received hemodialysis immediately before pitavastatin dosing and did not undergo hemodialysis during the pharmacokinetic study. Hemodialysis patients have 33 and 36% increases in the mean unbound fraction of pitavastatin as compared to healthy volunteers and patients with moderate renal impairment, respectively. In another pharmacokinetic study, patients with severe renal impairment (glomerular filtration rate 15-29 mL/min/1.73 m2) not receiving hemodialysis were administered a single dose of Pitavastatin 4 mg. The AUC0-inf and the Cmax were 36 and 18% higher, respectively, compared with those of healthy volunteers. For both patients with severe renal impairment and healthy volunteers, the mean percentage of protein-unbound pitavastatin was approximately 0.6%. The effect of mild renal impairment on pitavastatin exposure has not been studied.
Hepatic Impairment: The disposition of pitavastatin was compared in healthy volunteers and patients with various degrees of hepatic impairment. The ratio of pitavastatin Cmax between patients with moderate hepatic impairment (Child-Pugh B disease) and healthy volunteers was 2.7. The ratio of pitavastatin AUCinf between patients with moderate hepatic impairment and healthy volunteers was 3.8. The ratio of pitavastatin Cmax between patients with mild hepatic impairment (Child-Pugh A disease) and healthy volunteers was 1.3. The ratio of pitavastatin AUCinf between patients with mild hepatic impairment and healthy volunteers was 1.6. Mean pitavastatin t½ for moderate hepatic impairment, mild hepatic impairment, and healthy were 15, 10, and 8 hours, respectively.
Drug-Drug Interactions: The principal route of pitavastatin metabolism is glucuronidation via liver UGTs with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system.
Warfarin: The steady-state pharmacodynamics (international normalized ratio [INR] and prothrombin time [PT]) and pharmacokinetics of warfarin in healthy volunteers were unaffected by the co-administration of Pitavastatin 4 mg daily. However, patients receiving warfarin should have their PT time or INR monitored when pitavastatin is added to their therapy.
Indications/Uses
Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.
Primary Hypercholesterolemia and Mixed Dyslipidemia: Pitavastatin is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase HDL-C in adult patients with primary hyperlipidemia or mixed dyslipidemia.
Limitations of Use: Doses of Pitavastatin greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4 mg once daily dosing of Pitavastatin.
The effect of Pitavastatin on cardiovascular morbidity and mortality has not been determined.
Pitavastatin has not been studied in Fredrickson Type I, III, and V dyslipidemias.
Dosage/Direction for Use
General Dosing Information: The dose range for Pitavastatin is 1 to 4 mg orally once daily at any time of the day with or without food. The recommended starting dose is 2 mg and the maximum dose is 4 mg. The starting dose and maintenance doses of Pitavastatin should be individualized according to patient characteristics, such as goal of therapy and response.
After initiation or upon titration of Pitavastatin, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.
Dosage in Patients with Renal Impairment: Patients with moderate and severe renal impairment (glomerular filtration rate 30-59 mL/min/1.73 m2 and 15-29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of Pitavastatin 1 mg once daily and a maximum dose of Pitavastatin 2 mg once daily.
Use with Erythromycin: In patients taking erythromycin, a dose of Pitavastatin 1 mg once daily should not be exceeded.
Use with Rifampin: In patients taking rifampin, a dose of Pitavastatin 2 mg once daily should not be exceeded.
Or as prescribed by the physician.
Overdosage
There is no known specific treatment for Pitavastatin overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required.
Hemodialysis is unlikely to be of benefit due to high protein binding ratio of Pitavastatin.
Contraindications
The use of Pitavastatin is contraindicated in the following conditions: Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with Pitavastatin.
Patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.
Co-administration with cyclosporine.
Pregnancy.
Lactation. It is not known if pitavastatin is present in human milk; however, another drug in this class passes into breast milk. Since HMG-CoA reductase inhibitors have the potential for serious adverse reactions in breastfed infants, women who require pitavastatin treatment should not breastfeed their infants.
Special Precautions
Skeletal Muscle Effects: Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Pitavastatin. These risks can occur at any dose level, but increase in a dose-dependent manner.
Pitavastatin should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (≥65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy may also be increased with concurrent administration of fibrates or lipid-modifying doses of niacin. Pitavastatin should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin.
Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing Pitavastatin with colchicine.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
Pitavastatin therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Pitavastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Pitavastatin.
Liver Enzyme Abnormalities: Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including Pitavastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.
It is recommended that liver enzyme tests be performed before the initiation of Pitavastatin and if signs or symptoms of liver injury occur.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Pitavastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart Pitavastatin.
As with other HMG-CoA reductase inhibitors, Pitavastatin should be used with caution in patients who consume substantial quantities of alcohol. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of Pitavastatin.
Endocrine Function: Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Pitavastatin.
Renal Impairment: Patients with moderate and severe renal impairment (glomerular filtration rate 30-59 mL/min/1.73 m2 and 15-29 mL/min/1.73 m2 not receiving hemodialysis, respectively) as well as end-stage renal disease receiving hemodialysis should receive a starting dose of Pitavastatin 1 mg once daily and a maximum dose of Pitavastatin 2 mg once daily.
Hepatic Impairment: Pitavastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations of hepatic transaminase levels.
Use in Children: Safety and effectiveness of Pitavastatin in pediatric patients have not been established.
Use in Elderly: No significant differences in efficacy or safety were observed between elderly patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.
Use In Pregnancy & Lactation
Use in Pregnancy: Pitavastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with Pitavastatin during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Pitavastatin may cause fetal harm when administered to pregnant women. Pitavastatin should be discontinued as soon as pregnancy is recognized.
Use in Lactation: Risk Summary: Pitavastatin is contraindicated during breastfeeding. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Pitavastatin.
Females and Males of Reproductive Potential: Contraception: Females: Pitavastatin may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Pitavastatin.
Adverse Reactions
Rhabdomyolysis accompanied by myoglobinuria and acute renal failure and myopathy (including myositis); Liver enzyme abnormalities.
Other adverse reactions reported were arthralgia, headache, influenza, and nasopharyngitis.
The following abnormal laboratory tests were also reported: elevated creatine phosphokinase, hepatic transaminases, alkaline phosphatase, bilirubin, and glucose.
Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with Pitavastatin.
Postmarketing Experiences: The following adverse reactions were observed during post-approval use of Pitavastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions associated with Pitavastatin therapy reported since marketing introduction, regardless of causality assessment, 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, muscle spasms and peripheral neuropathy.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
Patient should seek medical attention immediately at the first sign of any adverse drug reaction.
Drug Interactions
Cyclosporine: Cyclosporine significantly increases Pitavastatin exposure. Co-administration of cyclosporine with Pitavastatin is contraindicated.
Erythromycin: Erythromycin significantly increased pitavastatin exposure. In patients taking erythromycin, a dose of Pitavastatin 1 mg once daily should not be exceeded.
Rifampin: Rifampin significantly increased pitavastatin exposure. In patients taking rifampin, a dose of Pitavastatin 2 mg once daily should not be exceeded.
Gemfibrozil: Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Pitavastatin with gemfibrozil should be avoided.
Other Fibrates: Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Pitavastatin should be administered with caution when used concomitantly with other fibrates.
Niacin: The risk of skeletal muscle effects may be enhanced when Pitavastatin is used in combination with niacin; a reduction in Pitavastatin dosage should be considered in this setting.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing Pitavastatin with colchicine.
Warfarin: Pitavastatin had no significant pharmacokinetic interaction with R- and S-warfarin. Pitavastatin had no significant effect on prothrombin time (PT) and international normalized ratio (INR) when administered to patients receiving chronic warfarin treatment. However, patients receiving warfarin should have their PT and INR monitored when pitavastatin is added to their therapy.
Storage
Store at temperatures not exceeding 30°C. Keep in a dry place.
ATC Classification
C10AA08 - pitavastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
FC tab 2 mg x 14's, 28's.
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