NIKP-Pitavastatin

NIKP-Pitavastatin tablet 2 mg is a slightly yellowish-red round biconvex film-coated tablet printed with Pitavastatin 2 mg NIKP on both sides.
Each tablet contains 2.0 mg of Pitavastatin Calcium Hydrate as Pitavastatin Calcium.
Excipients/Inactive Ingredients: Lactose, Magnesium Aluminometasilicate, Hydroxypropyl Cellulose, Hypromellose, Magnesium Stearate, Triethyl Citrate, Titanium Oxide, Anhydrous Silicic acid, Yellow Ferric Oxide, Carnauba wax, and Yellow no. 5. (See Table 1.)

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Pharmacologic Category: Antilipemic agent, HMG-CoA Reductase Inhibitors.
Pharmacology: Pharmacodynamics: Pitavastatin Calcium is a competitive inhibitor of 3-hydroxymethylglutaryl-CoA (HMGCoA) reductase, an enzyme that catalyzes the conversion of HMG CoA to mevalonate (an early and rate limiting step in cholesterol synthesis). Inhibition of HMG-CoA reductase result in reduction of hepatic cholesterol biosynthesis, which leads to a compensatory increase in the expression of low-density lipoprotein (LDL) receptors on hepatic cell surface and, subsequently, increased hepatic clearance of LDL-Cholesterol from blood.
Thus, Pitavastatin reduces serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo-B), and triglycerides concentrations, and increase serum high-density lipoprotein (HDL)-cholesterol concentrations in patients with primary hypercholesterolemia or mixed dyslipidemia. Sustained inhibition of cholesterol biosynthesis in the liver also decreases very low-density lipoprotein (VLDL)-cholesterol concentrations.
Pharmacokinetics: Absorption: T_max: Oral: 1 hour.
Bioavailability, oral, solution: 51%.
Effect of food: Decreased 39% to 43%: No significant effect on AUC.
Distribution: Volume of distribution (Vd): 148 L.
Protein binding, albumin and alpha 1-acid glycoprotein: 99%.
Metabolism: Liver: Extensive via glucuronidation.
Metabolite, lactone (major): Inactive.
Substrate of UGT1A3 and UGT2B7.
Excretion: Renal excretion: 15%.
Fecal: 79%.
Bile: Extensive.
Elimination half-life: 11 to 12 hours.
Pharmacokinetic in Special Populations: Geriatric: Data from a pharmacokinetics study indicate that peak plasma concentrations and area under the plasma concentration time-curve (AUC) of pitavastatin were 10 or 30% higher, respectively, in geriatric individuals (65 years of age or older) compared with younger adult.
Hepatic Impairment: Result of pharmacokinetic study indicate that peak plasma concentrations or AUC of pitavastatin were 1.3 or 1.6 fold higher, respectively. In patients with mild (Child-Pugh Class A) hepatic impairment compared with those in healthy individuals.
In patients with moderate (Child-Pugh Class B) hepatic impairment, peak plasma concentrations or AUC of pitavastatin were 2.7 or 3.8 fold higher, respectively compared with those in healthy volunteers.
In this study, the mean elimination half-life of pitavastatin in healthy, patients with mild hepatic impairment or moderate hepatic impairment was 8, 10 or 15 hours respectively.
Renal Insufficiency: Peak plasma concentration or AUC of Pitavastatin were 60 or 102% higher, respectively, in patients with moderate renal impairment (glomerular filtration rate [GFR] 30-59 mL/minute per 1.73 m²) not undergoing hemodialysis, peak plasma concentrations or AUC of pitavastatin were 18 or 36% higher, respectively.
In patients with end-stage renal disease (ESRD) undergoing hemodialysis, peak plasma concentrations or AUC of pitavastatin were 40 or 86% higher respectively, compared with those in healthy individuals. Patients undergoing hemodialysis have a 33 or 36% increase in the mean unbound fraction of pitavastatin compared with healthy individuals or patients with moderate renal impairment, respectively. The effect of mild renal impairment on pitavastatin exposure has not been established. (See Table 2.)

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Plasma concentration and pharmacokinetic parameters such as AUC and C_max may vary depending on study conditions including selection of subjects, body fluid sampling frequency/sampling time, etc. (See Figure 1.)

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When a single oral dose of NIKP-Pitavastatin tablet 1 mg or reference product (1.0 mg of pitavastatin calcium) was given to healthy male adults during fasting with a cross-over method, the plasma concentrations of pitavastatin were measured. In a statistical analysis for the obtained pharmacokinetic parameters (AUC, C_max), calculation results of 90% confidence intervals for the parameters were within a range between log (0.80) to log (1.25), demonstrated the bioequivalence of the two products.
Additionally, when a single dose of either NIKP-Pitavastatin tablet 2 mg and reference product (2.0 mg of pitavastatin calcium) were administered, similar bioequivalence results of both preparations were demonstrated. (See Table 3 and Figure 2.)

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Pharmacokinetic Confidence Intervals (N=36): Point estimates of geometric means and 90% confidence intervals for the ln-transformed Test/Reference ratios of: C_max: 107.22 (99.17-115.91%).
AUC_0→tlast: 110.05 (105.22-115.10%).
AU_0→∞: 109.73 (105.06-114.61%).
Conclusion: Point estimates of geometric means and the 90% confidence intervals for the ln-transformed ratios (Test/Reference) for the C_max, AUC_0→tlast, AUC_0→∞ of Pitavastatin were within the 80.00-125.00%. Therefore, the bioequivalence of NIKP-Pitavastatin tablet 2 mg and reference product can be concluded.

Hypercholesterolemia and familial hypercholesterolemia.
Primary hyperlipidemia 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 when response to diet and other measures is inadequate.

Recommended Dose: Adult: Initial Dosage: 2 mg once daily.
Maintenance dosage: 1 to 4 mg once daily.
Maximum dose: 4 mg once daily.
Dosage adjustment: After initiation or upon titration of Pitavastatin, lipid levels should be analyzed after 4 weeks and the dosage adjusted accordingly.
Geriatric Use: In clinical studies of pitavastatin, approximately 43% of patients were 65 years of age or older. No substantial differences in safety or efficacy relative to younger adults were observed but increased sensitivity in some older patients can not be ruled out.
The ACC/AHA cholesterol management guidelines states that initiation of statin therapy for primary prevention of ASCVD in patients older than 75 years of age requires consideration of additional factors including increasing comorbidities, safety, considerations, and priorities of care.
Thus, the potential for an ASCVD risk reduction, benefit, adverse effects, and drug interactions, along with patients' preferences, must be considered before initiating statin therapy in patients older than 75 years of age.
Paediatric Use: Safety and efficacy of Pitavastatin have not been established in pediatric patients younger than 18 years old of age.
Dosage adjustment in patients with renal insufficiency and concomitant with other medicines. (See Table 4.)

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Mode of Administration: Pitavastatin is administered orally once daily at any time of day, without regard to food.

The risk of severe myopathy increased with pitavastatin dosages exceeding 4 mg daily.
Adjustment for toxicity are described as follows.
Severe muscle symptoms or fatigue: Promptly discontinue use; evaluate CPK, creatinine, and urinalysis for myoglobinuria.
Mild to moderate muscle symptoms: Discontinue use until symptom can be evaluated; evaluate patients for conditions that may increase the risk for muscle symptoms (e.g hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia, rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution, resume the original dose or lower dose of pitavastatin. If muscle symptoms recur, discontinue pitavastatin use.

Active liver disease including unexplained, persistent evaluations in serum aminotransferase (transaminase) concentrations.
Women who are or may become pregnant.
Nursing women.
Concomitant use with cyclosporine (see Interactions).
Known hypersensitivity to Pitavastatin or any ingredient in the formulation.

According to Announcement of Ministry of Public Health Thailand, HMG CoA-Reductase inhibitor should be treated with cautions as follows.
Do not use in pregnancy and lactation.
Do not use in patient with liver disease.
Do not use medicine when muscle pain at the area of, gastrocnemius, back or body. Stop medicine and consult with physicians immediately.
Hepatic function test should be performed pre-dose and post-dose 6 and 12 months respectively. Hepatic function test should be monitored every 6 months. Stop medicine and consult physician when serum transaminases level exceeds 3 times of the upper limit of normal [ULN].
Carefully use during co-administration with digoxin, warfarin due to the level of medicine may be high and contribute to dangerous.
Risk of myopathy or rhabdomyolysis will be increased when co-administration with following medicines namely Azole antifungals group such as Ketoconazole, Itraconazole etc., Macrolides group such as Erythromycin, Clarithromycin etc., HIV protease inhibitors such as Indinavir, Ritonavir, Saquinavir etc., Verapamil, Diltiazem, Gemfibrozil, Nicotinic acid, Cyclosporine, Amiodarone etc.
Risk of rhabdomyolysis will be increased in following conditions for instance high dose of Pitavastatin calcium in elderly, hepatic impairment or renal impairment or chronic alcoholic or hypothyroidism.
Carefully use when co-administration with Colchicine especially elderly or patients with renal impairment due to there are risk of myopathy and rhabdomyolysis.
This medicine may increase risk of elevation of blood sugar.
With regard to information on influence of concomitant use of Pitavastatin with Colchicine, Digoxin, Enalapril, Erythromycin, Ezetimibe, Fibric acid derivative, Cyclosporin, Niacin and Warfarin in the next topic (see Interactions).

Pregnancy Category: X (See Contraindications and also Fetal/Neonatal Morbidity and Mortality as follows).
Fetal/Neonatal Morbidity and Mortality: Serum cholesterol and triglyceride concentrations increase during normal pregnancy and cholesterol products are essential for fetal development; therefore, suppression of cholesterol biosynthesis by pitavastatin during pregnancy may cause fetal harm.
Lactation: Pitavastatin is distributed into milk in rats, it is not known whether pitavastatin is distributed into human milk. Because of the potential for serious adverse reactions from pitavastatin in nursing infants, the drug is contraindicated in nursing women. Women who require pitavastatin therapy should be advised not to breast-feed their infants or advised to discontinue pitavastatin.
Women of childbearing potential should use effective contraceptive method during pitavastatin therapy. If the patients become pregnant while taking the drug, pitavastatin should be discontinued and the patients apprised of the potential fetal hazard and the lack of known clinical benefit with continued use during pregnancy.

Common Adverse Effects: Adverse effects reported in 2% or more of patients receiving pitavastatin including myalgia, back pain, diarrhea, constipation, and pain in extremity. Other adverse effect reported in clinical studies include arthralgia, headache, influenza, and nasopharyngitis. Laboratory abnormalities including increase in concentrations of CK, aminotransferases, alkaline phosphatase, bilirubin and glucose also have been reported.

Pitavastatin is minimally metabolized by hepatic cytochrome P450 (CYP) isoenzyme 2C9 and, to a lesser extent, by CYP2C8.
Colchicine: Myopathy, including rhabdomyolysis, has been reported in patients receiving various statins concomitantly with colchicine. Caution is advised when pitavastatin is used concomitantly with colchicine.
Digoxin: Concomitant use of pitavastatin (4 mg once daily) and digoxin (0.25 mg once daily for 7 days) decreased pitavastatin peak plasma concentration by 9% increased pitavastatin area under the plasma concentration-time curve (AUC) by 4% and decreased digoxin peak plasma concentration and AUC by 4 and 3% respectively.
Enalapril: Concomitant use of pitavastatin (4 mg once daily) and enalapril (20 mg once daily for 5 days) increased AUC of pitavastatin by 6% and decreased peak plasma concentration of the drug by 7%. Peak plasma concentration and AUC of enalapril were increased by 12%.
Erythromycin: Concomitant use of pitavastatin (4 mg as a single dose on day 4) and erythromycin (500 mg 4 times daily for 6 days), pitavastatin peak plasma concentration and AUC were increased by 3.6 and 2.8 fold, respectively; such effects were considered clinically important. The interaction between pitavastatin and erythromycin probably resulted partly from erythromycin-induced inhibition of OATP1B1-mediated hepatic uptake of pitavastatin. If used concomitantly with erythromycin, dosage of pitavastatin should not exceed 1 mg once daily.
Ezetimibe: Concomitant use of pitavastatin (2 mg once daily) and ezetimibe (10 mg for 7 days) decreased pitavastatin peak plasma concentration and AUC by 0.2 and 2% respectively, and increased ezetimibe peak plasma concentration and AUC by 2 and 9% respectively.
Fibric acid derivative: Concomitant use of statin and gemfibrozil increase the risk of myopathy or rhabdomyolysis. Concomitant use of pitavastatin (4 mg once daily) and gemfibrozil (600 mg twice daily for 7 days), pitavastatin peak plasma concentration and AUC were increased by 31 and 45% respectively.
Concomitant use of statin and other fibric derivatives (e.g. fenofibrate) increases the risk of myopathy, concomitant use of pitavastatin (4 mg once daily) and fenofibrate (160 mg once daily for 7 days), pitavastatin peak plasma concentration and AUC were increased by 11 and 18% respectively. The ACC/AHA Cholesterol Management Guidelines states that the combination of fenofibrate and low or moderate intensity statin therapy may be considered only if the benefits from Atherosclerotic Cardiovascular Disease (ASCVD) risk reduction or triglyceride lowering (when triglyceride concentration exceed 500 mg/dL) outweigh the potential risk of adverse effects.
Cyclosporine: Concomitant use of pitavastatin (2 mg once daily for 6 days) and cyclosporine (2 mg/kg on day 6), pitavastatin peak plasma concentration and AUC were increased by 6.6 and 4.6 fold respectively; such effect were considered clinically important. The interaction between pitavastatin and cyclosporine probably resulted partly from cyclosporine induced inhibition of OATP1B1-mediated hepatic uptake of pitavastatin. Concomitant use of pitavastatin with cyclosporine is contraindicated.
Niacin: Concomitant use of pitavastatin and antilipidemic dosages (1 g daily or higher) of niacin increases the risk of myopathy. Data from several large randomized studies indicate that concomitant use of niacin (1.5-2 g daily) with another statin (i.e., simvastatin 40-80 mg once daily, with or without ezetimibe results in an increase in risk of severe adverse effects, including disturbance in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, infection, and bleeding.
If pitavastatin is used concomitantly with antilipidemic dosages of niacin, caution is advised and reduction in pitavastatin dosages should be considered.
Warfarin: Pitavastatin had no clinical important pharmacokinetic interaction with R- and S- warfarin. Following concomitant use of pitavastatin (4 mg once daily for 9 days) and an individualized maintenance dosage of warfarin sodium (2-7 mg for 8 days), R-warfarin peak plasma concentration and AUC increased by 3% and 7% respectively and S-warfarin peak plasma concentration and AUC increased by 3% and 6% respectively. In addition, pitavastatin (4 mg once daily) had no clinically important effect on prothrombin time (PT) and international normalized ratio (INR) in patients receiving long-term warfarin therapy; however, the manufacturer and some experts recommend close monitoring of PT and INR after pitavastatin is initiated and whether there is a change in the statin dosage in patients receiving warfarin.

Store below 30°C and protect from light.

Dyslipidaemic Agents

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

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