Pitavastatin

Pitavastatin is an HMG-CoA reductase inhibitor belonging to Antilipidemic Agent.

Pitavastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke.

Pitavastatin peak plasma concentrations are achieved about 1hour after oral administration. The absolute bioavailability of pitavastatin oral solution is 51%. Pitavastatin is more than 99% protein bound in human plasma, mainly to albumin and alpha 1-acid glycoprotein, and the mean volume of distribution is approximately 148 L. The principal route of pitavastatin metabolism is glucuronidation via liver uridine 5'-diphosphate glucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. Pitavastatin is marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. 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.

Pitavastatin shows common side effects like Back pain, constipation, Diarrhea, memory loss or forgetfulness, confusion.

Pitavastatin is available in the form of an Oral Tablet.

Pitavastatin is available in India, US, UK, Singapore, Russia, Spain, Mexico, Italy, Japan, South Korea and China.

Pitavastatin belongs to the Antilipidemic Agent acts as a HMG-CoA Reductase Inhibitor.

Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the biosynthetic pathway for cholesterol. 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. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very low-density lipoproteins.

The Data of onset and duration of action of Pitavastatin is not clinically established.

The Tmax of Pitavastatin is approximately 1 hours.

Pitavastatin is available in the form Oral Tablet.

Pitavastatin Tablet is taken orally, usually once daily.

Pitavastatin is used to reduce the levels of bad cholesterol and triglycerides in the blood. It is also used to prevent long-term cardiovascular risks such as strokes and heart attacks. Patients are advised to follow a strict diet and exercise regimen along with Pitavastatin for the best possible effect.

Pitavastatin is an HMG-CoA reductase inhibitor belonging to Antilipidemic Agent.

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.

Pitavastatin is approved for use in the following clinical indications

Adult indication

• Heterozygous familial hypercholesterolemia
• Prevention of atherosclerotic cardiovascular disease

Pediatric indication

• Heterozygous familial hypercholesterolemia

Adult Dose

• Heterozygous familial hypercholesterolemia

Patients unable to tolerate high-intensity therapy

Moderate-intensity therapy: Oral: 1 to 4 mg once daily.

• Prevention of atherosclerotic cardiovascular disease
• Primary prevention:

Patients without diabetes, age 40 to 75 years, and LDL-C 70 to 189 mg/dL

ASCVD 10-year risk 5% to <7.5%:

Moderate-intensity therapy: Oral: 1 to 4 mg once daily to reduce LDL-C by 30% to 49%.

ASCVD 10-year risk ≥7.5% to <20%:

Moderate-intensity therapy: Oral: 1 to 4 mg once daily to reduce LDL-C by 30% to 49%; higher risk patients with multiple risk-enhancing factors may benefit from high-intensity statin therapy (ie, with atorvastatin or rosuvastatin) to reduce LDL-C by ≥50%.

ASCVD 10-year risk ≥20% (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 1 to 4 mg once daily.Patients with diabetes

Age 40 to 75 years without additional ASCVD risk factors:

Moderate-intensity therapy: Oral: 1 to 4 mg once daily to reduce LDL-C by 30% to 49%.

ASCVD 10-year risk ≥20% or multiple ASCVD risk factors (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 1 to 4 mg once daily.

Patients with LDL-C ≥190 mg/dL and age 20 to 75 years (regardless of ASCVD risk estimate or coexisting diabetes mellitus) (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 1 to 4 mg once daily.

• Secondary prevention in patients with established ASCVD (eg, coronary heart disease, cerebrovascular disease [ischemic stroke or transient ischemic attack], peripheral arterial disease) (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate doses of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 1 to 4 mg once daily.

Pediatric Dose

• Heterozygous familial hypercholesterolemia

Children ≥8 years and Adolescents: Pitavastatin (pitavastatin calcium)

Initial: 2 mg once daily; evaluate lipids after 4 weeks and titrate dose accordingly.

Maximum daily dose: 4 mg/day; lipid levels should be evaluated 4 weeks after any dose adjustment.

Pitavastatin is available in various strengths as 1mg, 2mg and 4mg.

Pitavastatin is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient

GFR ≥60 mL/minute/1.73 m²: There are no dosage adjustments provided.

GFR 15 to 59 mL/minute/1.73 m² (not receiving hemodialysis): Initial: 1 mg once daily; maximum: 2 mg/day.

ESRD receiving hemodialysis: Initial: 1 mg once daily; maximum: 2 mg/day.

• Dosage Adjustment in Hepatic impairment Patient

Contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.

Pitavastatin is contraindicated in patients with

• Known hypersensitivity to pitavastatin or any inactive ingredient in Pitavastatin. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with Pitavastatin.
• Concomitant use of cyclosporine.
• Active liver disease including unexplained persistent elevations of hepatic transaminase levels.
• 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, females who require pitavastatin treatment should not breastfeed their infants.

• Myopathy and Rhabdomyolysis

Pitavastatin may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred because of rhabdomyolysis with statin use, including Pitavastatin.

• Immune-Mediated Necrotizing Myopathy

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; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.

• Hepatic Dysfunction

Increases in serum transaminases have been reported with Pitavastatin. In most cases, the elevations were transient and either resolved or improved on continued therapy or after a brief interruption in therapy. There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Pitavastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before the initiation of Pitavastatin and thereafter, when clinically indicated. Pitavastatin is contraindicated in patients with active liver disease including unexplained persistent elevations in hepatic transaminase levels. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue Pitavastatin.

• Increases in HbA1c and Fasting Serum Glucose Levels

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Pitavastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

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 LIVALO.

Pitavastatin is contraindicated in pregnant females. There are reports of congenital anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy; however, maternal disease, differences in specific agents used, and the low rates of exposure limit the interpretation of the available data. Cholesterol biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase normally during pregnancy. The discontinuation of lipid lowering medications temporarily during pregnancy is not expected to have significant impact on the long term outcomes of primary hypercholesterolemia treatment. Pitavastatin should be discontinued immediately if an unplanned pregnancy occurs during treatment.

Common Adverse effects

• Constipation, diarrhea, Back pain, myalgia, Influenza, Headache, Arthralgia, Nasopharyngitis.

Rare Adverse effects

• Chest pain, Acute generalized exanthematous pustulosis, Elevated glycosylated hemoglobin, increased serum glucose, Abdominal distress, abdominal pain, dyspepsia, nausea, Erectile dysfunction, Hepatic failure, hepatitis, increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases, jaundice, Angioedema, hypersensitivity reaction, Asthenia, depression, dizziness, fatigue, hypoesthesia, insomnia, malaise, peripheral neuropathy, Increased creatine phosphokinase in blood specimen, muscle spasm, myopathy, rhabdomyolysis, Interstitial pulmonary disease.

• Cyclosporine

Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis.

• Gemfibrozil

Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with statins, including Pitavastatin.

• Erythromycin

Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis.

• Rifampin

Rifampin significantly increases peak pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis.

• Fibrates

Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins, including Pitavastatin.

• Niacin

The risk of myopathy and rhabdomyolysis may be increased with concomitant use of lipid modifying doses (≥1 g/day) of niacin with Pitavastatin.

• Colchicine

Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with statins, including Pitavastatin.

The common side effects of Pitavastatin include the following

• Common

Back pain, constipation, Diarrhea, memory loss or forgetfulness, confusion.

• Rare

Muscle pain, tenderness, or weakness, fever, Nausea, extreme tiredness, unusual bleeding or bruising, lack of energy, weakness, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, dark urine, flu-like symptoms, rash, itching, hives.

• Pregnancy

Pregnancy Category

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. Limited published data on the use of Pitavastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no embryo-fetal toxicity or congenital malformations were observed when pregnant rats and rabbits were orally administered pitavastatin during organogenesis at exposures which were 22 and 4 times, respectively, the maximum recommended human dose (MRHD). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

• Nursing Mothers

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.

• Pediatric Use

The safety and effectiveness of Pitavastatin as an adjunctive therapy to diet to reduce elevated TC, LDL-C, and Apo Bin pediatric patients aged 8 years and older with HeFH have been established. Use of Pitavastatin for this indication is supported by a 12-week, double-blind, placebo-controlled trial in 82 pediatric patients 8 to 16 years of age with HeFH and a 52-week open-label trial in 85 pediatric patients with HeFH. The safety and effectiveness of Pitavastatin have not been established in pediatric patients younger than 8 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).

• Geriatric Use

In controlled clinical studies, 1,209(43%) patients were 65years and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Advanced age(≥65years) is a risk factor for myopathy and rhabdomyolysis. In general, dose selection for a geriatric patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.

No specific treatment for Pitavastatin overdose is known. Contact Poison Control (1-800-222-1222) for latest recommendations. Hemodialysis is unlikely to be of benefit due to high protein binding ratio of Pitavastatin.

Pharmacodynamic

Cardiac Electrophysiology In a randomized, double-blind, placebo-controlled, 4-way parallel, active-comparator study with moxifloxacin in 174 healthy participants, Pitavastatin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 16 mg (4 times the recommended maximum dose of 4 mg daily).

Pharmacokinetics

• Absorption

Pitavastatin peak plasma concentrations are achieved about 1hour after oral administration. Both Cmax and AUC0-inf increased in an approximately dose-proportional manner for single Pitavastatin doses from 1 mg to 24 mg once daily. The absolute bioavailability of pitavastatin oral solution is 51%.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 alpha 1-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

The principal route of pitavastatin metabolism is glucuronidation via liver uridine 5'-diphosphate glucuronosyltransferase (UGT) with subsequent formation of pitavastatin lactone. There is only minimal metabolism by the cytochrome P450 system. 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 UGTs (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.

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