Pitavastor (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Whan In Pharm., Co. Ltd. (Republic Of Korea)

Contact Information

TEVA (Israel)

ATC Code

C10AA08 (Pitavastatin)

Active Substance

Pitavastatin (Rec.INN registered by WHO)

Dosage Forms

	Pitavastor	Film-coated tablets, 1 mg: 28 or 98 pcs.
		Film-coated tablets, 2 mg: 28 or 98 pcs.
		Film-coated tablets, 4 mg: 28 or 98 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets, white, round, with a score on one side and the inscription “1” on the other side.

Excipients: lactose monohydrate – 50.355 mg, povidone K-30, low-substituted hydroxypropyl cellulose, heavy magnesium carbonate, magnesium stearate.

Film coating composition Opadry white (02F680007): hypromellose, titanium dioxide, polyethylene glycol/macrogol, talc.

14 pcs. – blisters (2) – cardboard packs^×.
14 pcs. – blisters (7) – cardboard packs^×.

Film-coated tablets, white, round, with a score on one side and the inscription “2” on the other side.

Excipients: lactose monohydrate – 100.71 mg, povidone K-30, low-substituted hydroxypropyl cellulose, heavy magnesium carbonate, magnesium stearate.

Film coating composition Opadry white (02F680007): hypromellose, titanium dioxide, polyethylene glycol/macrogol, talc.

14 pcs. – blisters (2) – cardboard packs^×.
14 pcs. – blisters (7) – cardboard packs^×.

Film-coated tablets, white, round, with a score on one side and the inscription “4” on the other side.

Excipients: lactose monohydrate – 201.42 mg, povidone K-30, low-substituted hydroxypropyl cellulose, heavy magnesium carbonate, magnesium stearate.

Film coating composition Opadry white (02F680007): hypromellose, titanium dioxide, polyethylene glycol/macrogol, talc.

14 pcs. – blisters (2) – cardboard packs^×.
14 pcs. – blisters (7) – cardboard packs^×.

^× protective stickers may be additionally applied.

Clinical-Pharmacological Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacotherapeutic Group

Hypolipidemic agents; HMG-CoA reductase inhibitors

Pharmacological Action

Mechanism of action

Pitavastatin is a competitive inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, the enzyme that catalyzes the initial stage of cholesterol synthesis, the formation of mevalonic acid from HMG-CoA. Since the conversion of HMG-CoA to mevalonic acid is the initial stage of cholesterol synthesis, the use of pitavastatin does not cause the accumulation of potentially toxic sterols in the body. HMG-CoA is metabolized to acetyl-CoA, which is involved in many synthesis processes in the body.

Pharmacodynamic effects

The efficacy of pitavastatin in reducing plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG), and apolipoprotein B (Apo-B), as well as increasing high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (Apo-A1) levels has been proven (see Table 1).

Table 1. Dose response in patients with primary hypercholesterolemia

(adjusted mean percent change from baseline)

*unadjusted

Clinical efficacy

In the treatment of primary hypercholesterolemia and combined (mixed) dyslipidemia, when prescribed at therapeutic doses, Pitavastatin significantly reduced LDL-C, TC, non-HDL-C, TG, and Apo-B levels and increased HDL-C and Apo-A1 levels. The TC/HDL-C and Apo-B/Apo-A1 ratios decreased. When using pitavastatin at a dose of 2 mg, a reduction in LDL-C concentration of 38-39% was achieved, and 44-45% when using a dose of 4 mg. In most cases, when prescribing a dose of 2 mg, the target LDL-C treatment level according to the European Atherosclerosis Society (EAS) recommendations was achieved.

In the treatment of elderly patients (≥65 years) with primary hypercholesterolemia and mixed dyslipidemia when prescribed pitavastatin at a dose of 1, 2, or 4 mg, LDL-C values decreased by 31%, 39.0%, and 44.3%, respectively. The target level set by EAS was achieved in 90% of patients.

In the treatment of patients with primary hypercholesterolemia or mixed dyslipidemia in combination with 2 or more cardiovascular risk factors, or mixed dyslipidemia in combination with type 2 diabetes mellitus, about 80% of patients achieved target LDL-C levels. LDL-C levels in these patient groups decreased by 44% and 41%, respectively.

Atherosclerosis

In the treatment of patients who underwent percutaneous coronary intervention for acute coronary syndrome under intravascular ultrasound control, the administration of pitavastatin at a dose of 4 mg for 8-12 months led to a reduction in coronary plaque volume by approximately 17% and was accompanied by reverse remodeling of the vascular wall (from 113.0 to 105.4 mm³).

Diabetes mellitus

In patients with hyperlipidemia and impaired glucose tolerance, when prescribed pitavastatin at doses of 1 mg/day or 2 mg/day in addition to lifestyle modification recommendations, newly diagnosed diabetes mellitus developed less frequently than in patients not receiving lipid-lowering therapy: 39.9% versus 45.7% over a period of 2.8 years, the hazard ratio was 0.82.

Data from a meta-analysis of the safety of pitavastatin regarding the risk of developing diabetes mellitus demonstrated a neutral effect of pitavastatin on the risk of new cases of diabetes mellitus.

Pediatric patients

In children and adolescents at high risk of hyperlipidemia (fasting plasma LDL-C level ≥160 mg/dL (4.1 mmol/L), or LDL-C≥130 mg/dL (3.4 mmol/L) with additional risk factors), administration of pitavastatin at a dose of 1 mg, 2 mg, 4 mg once daily for 12 weeks reduced LDL-C by 23.5%, 30.1%, and 39.3%, respectively.

In children and adolescents at high risk of hyperlipidemia taking Pitavastatin for 52 weeks, the mean LDL-C level decreased to 37.8%. 47 patients (42.0%) achieved the target LDL-C value of <130 mg/dL and 23 patients (20.5%) achieved the optimal LDL-C value of <110 mg/dL. The reduction in mean LDL-C was 40.2% in the group of patients aged 6-10 years (n=42), 36.7% in the group aged 10-16 years (n=61), and 34.5% in the group aged 16-17 years (n=9). The patient's response to pitavastatin therapy did not depend on the patient's gender. The mean TC level decreased by 29.5%, and the mean TG level decreased by 7.6% by the end of the study.

HIV population

The effect of pitavastatin and other statins on LDL-C levels in HIV-infected patients with dyslipidemia is reduced, or this treatment is comparable to the treatment of patients with primary hypercholesterolemia and mixed dyslipidemia without HIV.

In HIV-infected patients taking 4 mg of pitavastatin once daily, LDL-C levels decreased by 31% after 12 weeks and by 30% after 52 weeks of therapy.

Pharmacokinetics

Absorption

Pitavastatin is rapidly absorbed in the upper gastrointestinal tract, C_max in plasma is reached within 1 hour after administration. Food intake does not affect absorption. The C_max of pitavastatin in plasma decreases by 43% when taken concomitantly with fatty food, but the AUC remains unchanged. The unchanged drug undergoes enterohepatic recirculation and is well absorbed from the jejunum and ileum. The absolute bioavailability of pitavastatin is 51%.

Distribution

More than 99% of pitavastatin binds to plasma proteins, mainly albumin and alpha-1 acid glycoprotein. The mean volume of distribution is 133 L. Pitavastatin actively penetrates hepatocytes via OATP1B1 and OATP1B3 transport proteins. The AUC varies within a 4-fold increase from the minimum to the maximum value. Pitavastatin is not a substrate for P-glycoprotein.

Biotransformation

Plasma contains mainly unchanged Pitavastatin. The main metabolite is an inactive lactone, which is formed from the conjugate of Pitavastatin glucuronide of the ester type with the participation of UDP-glucuronosyltransferases (UGT1A3 and 2B7). Cytochrome P450 minimally influences the metabolism of pitavastatin. The CYP2C9 isoenzyme (and to a lesser extent the CYP2C8 isoenzyme) is involved in the metabolism of pitavastatin to minor metabolites.

Elimination

Pitavastatin is rapidly excreted unchanged from the liver with bile but undergoes enterohepatic recirculation, which provides its long-lasting effect. Less than 5% of pitavastatin is excreted by the kidneys. T_1/2 from plasma varies from 5.7 h (single dose) to 8.9 h (at steady state), the mean clearance is 43.4 L/h after a single oral dose.

Pharmacokinetics in different patient groups

Elderly patients. When assessing the pharmacokinetics of pitavastatin in elderly patients over 65 years of age, the AUC of pitavastatin was 1.3 times higher. This did not affect efficacy or safety.

Hepatic impairment. In patients with mild hepatic impairment (Child-Pugh class A), the AUC was 1.6 times higher than in healthy volunteers, while in patients with moderate hepatic impairment (Child-Pugh class B), the AUC was 3.9 times higher. In severe hepatic impairment, the use of pitavastatin is contraindicated.

Renal impairment. In patients with moderate renal impairment and those on hemodialysis, an increase in AUC of 1.8 times and 1.7 times, respectively, was noted.

Gender differences. An increase in AUC in women compared to men by 1.6 times was noted in a study of healthy volunteers, which did not affect the efficacy and safety of pitavastatin.

Race. According to the results of a pharmacokinetic analysis of data obtained from healthy volunteers of different races (Japanese and Caucasian populations), factors such as gender and age did not affect the pharmacokinetics of pitavastatin.

Pediatric patients. Pharmacokinetic data regarding use in children and adolescents are limited. Selective sampling revealed a dose-dependent dynamics of pitavastatin concentration in plasma 1 hour after dose administration. It was also noted that the concentration of pitavastatin 1 hour after dose administration was inversely related to body weight and could be higher in children than in adults.

Indications

• For the reduction of elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in adults, adolescents and children aged 6 years and older with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson type IIa hyperlipidemia), or mixed hypercholesterolemia (Fredrickson type IIb hyperlipidemia) as an adjunct to diet, when diet and other non-pharmacological treatments (e.g., exercise, weight loss) are insufficient.

ICD codes

Dosage Regimen

Before starting and during treatment, patients should adhere to a cholesterol-lowering diet.

Dosage regimen

Adults

The initial dose of the drug is 1 mg once daily. If necessary, the drug dose can be increased at intervals of at least 4 weeks to 2 mg/day. The dose should be individually adjusted according to LDL-C concentrations, treatment goals, and patient response to treatment. Most patients require a dose of 2 mg. The maximum daily dose is 4 mg.

Special patient groups

Patients with mild and moderate hepatic impairment.

A maximum daily dose of 2 mg is recommended.

Patients with renal impairment.

In mild renal impairment (it is advisable to objectively assess this degree with reflection of CC or GFR), the drug Pitavastor should be used with caution. Data on the use of the maximum daily dose of 4 mg in renal impairment of any severity are limited, therefore, prescribing the maximum daily dose of 4 mg should only be done with careful monitoring of renal function after gradual dose increase. It is not recommended to prescribe the maximum daily dose of 4 mg to patients with severe renal impairment; it is recommended to consider limiting the maximum daily dose to 2 mg in severe renal failure.

Elderly patients.

Dose adjustment is not required.

Children and adolescents over 6 years old

The use of the drug Pitavastor in children is only possible under the constant supervision of a physician experienced in the treatment of hyperlipidemia and the prescription of statins in childhood.

In children and adolescents with heterozygous hereditary hypercholesterolemia, the standard initial dose is 1 mg once daily. Dose adjustment should be made at intervals of 4 or more weeks. Doses should be individually selected according to LDL-C levels, therapy goals, and patient response to treatment. In children from 6 to 9 years old, the maximum daily dose is 2 mg. In children from 10 years and older, the maximum daily dose is 4 mg.

Children under 6 years

The safety and efficacy of the drug Pitavastor for children under 6 years have not been studied.

Method of administration

Orally, regardless of meals. The tablets should be swallowed whole, preferably with water.

It is preferable to take the tablets at the same time of day, preferably in the evening, in accordance with the circadian rhythm of lipid metabolism.

Adverse Reactions

Summary of the safety profile

In controlled clinical trials, at recommended doses, less than 4% of patients receiving pitavastatin treatment were excluded from the study due to the development of adverse events. The most frequently reported adverse reaction was myalgia.

Summary of adverse reactions

Depending on the frequency of occurrence, the following adverse reactions are distinguished: very common (≥10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000) and frequency unknown (available data do not allow determining the frequency).

Blood and lymphatic system disorders uncommon – anemia.

Metabolism and nutrition disorders uncommon – anorexia.

Psychiatric disorders common – sleep disorder (insomnia).

Nervous system disorders common – headache; uncommon – dizziness, taste disturbance, somnolence; frequency unknown – myasthenia gravis.

Eye disorders rare – decreased visual acuity; frequency unknown – ocular myasthenia.

Ear and labyrinth disorders uncommon – tinnitus.

Gastrointestinal disorders common – constipation, diarrhea, dyspepsia, nausea; uncommon – abdominal pain, dry mouth, vomiting; rare – glossodynia, acute pancreatitis.

Hepatobiliary disorders uncommon – increased transaminase levels (AST, ALT); rare – cholestatic jaundice.

Skin and subcutaneous tissue disorders uncommon – pruritus, rash; rare – urticaria, erythema.

Musculoskeletal and connective tissue disorders common – myalgia, arthralgia; uncommon – muscle spasms; frequency unknown – immune-mediated necrotizing myopathy.

Renal and urinary disorders uncommon – pollakiuria.

General disorders and administration site conditions uncommon – asthenia, malaise, fatigue, peripheral edema.

Laboratory parameters in controlled clinical trials, after taking pitavastatin, an increase in creatine kinase activity to 3 times the ULN was observed in 49 out of 2800 patients (1.8%). Exceedances of ULN by 10 times or more with concomitant muscle symptoms were rare and observed only in one patient out of 2406 patients receiving 4 mg of pitavastatin (0.04%) in the clinical trial program.

Children

The clinical safety database includes safety data for 142 pediatric patients receiving Pitavastatin, including 87 patients aged 6 to 11 years, 55 patients aged 12 to 17 years. A total of 91 patients took Pitavastatin for 1 year, 12 patients took Pitavastatin for 2.5 years and 2 patients for 3 years. Less than 3% of patients receiving pitavastatin treatment were excluded from the study due to adverse events. The most frequently observed adverse reactions associated with pitavastatin in the clinical trial program were headache (4.9%), myalgia (2.1%), and abdominal pain (4.9%). Based on available data, the frequency, type, and severity of adverse reactions are assumed to be the same for children and adolescents as for adults.

Post-registration Use Experience

A two-year prospective post-registration surveillance study of 20,000 patients was conducted in Japan. The vast majority of these patients received Pitavastatin at a dose of 1 or 2 mg, but not 4 mg. Adverse events for which a causal relationship with pitavastatin could not be excluded were reported in 10.4% of patients, and 7.4% of patients discontinued treatment due to the development of adverse events. The incidence of myalgia was 1.08%. Most adverse events were mild. Over the 2-year period, the incidence of adverse events was higher in patients with a history of drug allergy (20.4%) or liver or kidney disease (13.5%).

Adverse reactions and their incidence observed in the prospective post-registration surveillance study, but not in international controlled clinical trials, when using the drug at recommended doses, are listed below.

Hepatobiliary disorders rarely – impaired liver function, liver disease.

Musculoskeletal and connective tissue disorders rarely – myopathy, rhabdomyolysis. In the post-registration surveillance study, there were two reports of rhabdomyolysis requiring hospitalization (0.01% of patients). In addition, there are spontaneous reports of musculoskeletal effects, including myalgia and myopathy, in patients treated with pitavastatin at all recommended doses. Reports of rhabdomyolysis with and without acute renal failure, including fatal rhabdomyolysis, have also been received.

Spontaneous reports of the following adverse events have also been received (frequency is based on cases observed in post-registration studies).

Nervous system disorders uncommon – hypoesthesia.

Gastrointestinal disorders rarely – abdominal discomfort.

Adverse events with other statins

• Sleep disorders, including nightmares;
• Amnesia;
• Sexual dysfunction;
• Depression;
• Interstitial lung disease, especially with long-term treatment;
• Diabetes mellitus: the incidence depends on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, body mass index >30 kg/m², elevated TG levels, history of arterial hypertension).

Contraindications

• Hypersensitivity to pitavastatin, other HMG-CoA reductase inhibitors (statins) and/or any of the excipients of the drug;
• Severe hepatic impairment (more than 9 points on the Child-Pugh scale) or Child-Pugh class C, active liver disease, including persistent elevation of serum “liver” transaminases (more than 3 times the upper limit of normal (ULN);
• Myopathy;
• Concomitant use of cyclosporine;
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

The use of Pitavastor during pregnancy is contraindicated. Women of childbearing potential should use reliable methods of contraception while being treated with Pitavastor. Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefit of treatment during pregnancy. Animal studies have shown that Pitavastatin has reproductive toxicity, but without teratogenic potential. If a patient is planning a pregnancy, treatment should be discontinued at least one month before conception. If pregnancy occurs during the use of Pitavastor, treatment should be discontinued immediately.

Breastfeeding period

The use of Pitavastor during breastfeeding is contraindicated. Pitavastatin is excreted in the milk of lactating rats. Data on the excretion of pitavastatin in human breast milk are not available. If it is necessary to use Pitavastor during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindication: severe hepatic impairment (more than 9 points on the Child-Pugh scale) or Child-Pugh class C, active liver disease, including persistent elevation of serum liver transaminases (more than 3 times the ULN).

For patients with mild to moderate hepatic impairment, the maximum recommended daily dose is 2 mg.

Use in Renal Impairment

Pitavastor should be used with caution in patients with moderate or severe renal impairment. The dose should be increased only with careful monitoring. The 4 mg dose is not recommended for patients with severe renal impairment.

Pediatric Use

In children over 6 years of age, it is used according to indications and in accordance with the dosing regimen.

The safety and efficacy of Pitavastor in children under 6 years of age have not been studied.

Geriatric Use

Dosage adjustment is not required.

Special Precautions

Effects on muscle tissue

As with other HMG-CoA reductase inhibitors (statins), there is a possibility of developing myalgia, myopathy, and, in rare cases, rhabdomyolysis. Patients should be advised to report any muscle symptoms. Creatine phosphokinase (CPK) activity should be measured in any patient reporting muscle pain, muscle tenderness on palpation, or weakness, especially if accompanied by malaise or fever.

CPK activity should not be measured after physical exertion or in the presence of any other possible causes of increased CPK that may distort the result. If CPK activity is elevated (5 times the ULN), a control test should be performed within 5-7 days.

Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been observed during treatment or after discontinuation of statin therapy. IMNM clinically presents as persistent proximal muscle weakness and elevated serum CPK, which persist despite statin discontinuation.

Pitavastor should not be used concomitantly with fusidic acid preparations (orally or by injection) or within 7 days after stopping treatment with drugs containing fusidic acid. In patients for whom the use of fusidic acid preparations is considered essential, statin therapy should be discontinued for the entire duration of treatment with this group of drugs. Cases of rhabdomyolysis (including several fatalities) have been observed in patients taking fusidic acid and statins concomitantly. Patients should be advised to seek immediate medical attention if they develop any symptoms characterized by muscle weakness, pain, or tenderness.

Statin therapy can be resumed 7 days after the last dose of fusidic acid. In exceptional cases, where long-term systemic use of fusidic acid preparations is necessary, for example, for the treatment of severe infections, the decision on the concomitant use of Pitavastor and fusidic acid should be made on an individual basis under close medical supervision.

Before treatment

Like all statins, Pitavastor should be prescribed with caution to patients with predisposing factors for the development of rhabdomyolysis. CPK activity should be determined to establish a baseline reference value in the following cases

• Renal impairment;
• Hypothyroidism;
• Personal or family history of hereditary muscle diseases;
• Previous history of muscle toxicity when treated with fibrates or other statins;
• History of liver disease or alcohol abuse;
• Patients over 70 years of age with other predisposing risk factors for rhabdomyolysis.

In such cases, clinical monitoring is recommended, and the risk of treatment should be weighed against the potential benefit. Treatment with Pitavastor should not be initiated if CPK activity is 5 times the ULN.

During treatment

The patient should be advised to immediately report any muscle pain, weakness, or cramps to the physician. CPK activity should be determined, and treatment should be discontinued if CPK activity is elevated (5 times the ULN). Discontinuation of treatment should be considered if severe muscle symptoms occur, even if CPK does not exceed 5 times the ULN. If symptoms resolve and CPK activity returns to normal, re-initiation of Pitavastor at a dose of 1 mg with careful monitoring may be considered.

Myasthenia gravis, ocular myasthenia

HMG-CoA reductase inhibitors (statins) have been reported in a few cases to cause de novo or exacerbate pre-existing generalized myasthenia gravis or ocular myasthenia (see section “Adverse Reactions”). If symptoms of myasthenia occur or worsen, Pitavastor should be discontinued. Recurrence of myasthenia upon re-administration of the same statin and upon use of another HMG-CoA reductase inhibitor has also been reported.

Effects on the liver

Like all statins, Pitavastor should be prescribed with caution to patients with a history of liver disease or patients who regularly consume excessive amounts of alcohol. Liver function tests should be performed before starting treatment with Pitavastor and periodically during treatment. Treatment with Pitavastor should be discontinued in patients with persistent elevation of “liver” transaminases (ALT and AST) exceeding 3 times the ULN.

Effects on the kidneys

Pitavastor should be used with caution in patients with moderate or severe renal impairment. The dose should be increased only with careful monitoring. The 4 mg dose is not recommended for patients with severe renal impairment.

Diabetes mellitus

Some evidence suggests that statins, as a class, lead to an increase in blood glucose levels, increasing the risk of developing diabetes in the future, and in some patients at high risk of developing diabetes, may lead to a level of hyperglycemia where formal treatment for diabetes becomes indicated. However, this risk is outweighed by the reduction in vascular risk with statin treatment and therefore should not be a reason to discontinue statin therapy. Patients at risk of hyperglycemia (fasting glucose from 5.6 to 6.9 mmol/L, BMI >30 kg/m², elevated TG levels, hypertension) require clinical and biochemical monitoring in accordance with national guidelines. At the same time, based on the results of both post-marketing safety surveillance and prospective studies, no confirmed signals of diabetes risk with pitavastatin use have been identified.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported with the use of some statins, especially with long-term therapy.

Observed clinical signs include dyspnea, non-productive cough, and deterioration in general health (increased fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Children

There are limited data on the long-term effects on growth and puberty in pediatric patients over 6 years of age taking Pitavastor. Adolescent girls should be counseled on the use of reliable contraceptive methods during treatment with Pitavastor.

Excipients

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effect on ability to drive and use machines

Caution should be exercised when driving vehicles or performing other work requiring increased attention, as adverse reactions such as dizziness and drowsiness may occur when taking Pitavastor.

Overdose

There is no specific treatment for overdose.

Symptomatic therapy should be provided, and CPK activity and liver function should be monitored. Hemodialysis is not effective.

Drug Interactions

Pitavastatin is actively transported into human hepatocytes by numerous hepatic transporters (including the organic anion transporting polypeptide [OATP]), which may be involved in some of the following interactions.

Cyclosporine

Concomitant administration of a single dose of cyclosporine with pitavastatin at steady state resulted in a 4.6-fold increase in the AUC of pitavastatin. The effect of cyclosporine at steady state on pitavastatin at steady state is unknown. Pitavastor is contraindicated in patients receiving treatment with cyclosporine.

Erythromycin

Concomitant administration of erythromycin with pitavastatin resulted in a 2.8-fold increase in the AUC of pitavastatin. Temporary discontinuation of pitavastatin is recommended during treatment with erythromycin or other macrolide antibiotics.

Gemfibrozil and other fibrates

In rare cases, fibrate monotherapy has been associated with the development of myopathy. Concomitant use of fibrates with statins has been associated with an increased incidence of myopathy and rhabdomyolysis. Caution should be exercised when using pitavastatin concomitantly with fibrates. In pharmacokinetic studies, concomitant use of pitavastatin with gemfibrozil resulted in a 1.4-fold increase in the AUC of pitavastatin and a 1.2-fold increase in the AUC of fenofibrate.

Nicotinic acid (in lipid-lowering doses)

An interaction study with pitavastatin and nicotinic acid in lipid-lowering doses (more than 1 g/day) has not been conducted. The use of nicotinic acid in monotherapy has been associated with the development of myopathy and rhabdomyolysis. Therefore, when used concomitantly with nicotinic acid in lipid-lowering doses (more than 1 g/day), Pitavastor should be prescribed with caution.

Fusidic acid

The risk of myopathy, including rhabdomyolysis, may be increased with the concomitant use of fusidic acid preparations (orally or by injection) and statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or a combination of both) remains unknown. Cases of rhabdomyolysis (including several fatalities) have been reported in patients receiving this combination. If treatment with fusidic acid preparations is necessary, therapy with Pitavastor should be discontinued for the entire duration of treatment with fusidic acid.

Rifampicin

Concomitant administration of rifampicin with pitavastatin resulted in a 1.3-fold increase in the AUC of pitavastatin due to reduced hepatic uptake.

Protease inhibitors and non-nucleoside reverse transcriptase inhibitors

Concomitant simultaneous use of lopinavir/ritonavir, darunavir/ritonavir, atazanavir, or efavirenz with pitavastatin resulted in minor changes in the AUC of pitavastatin.

Ezetimibe and its glucuronide metabolite

They inhibit the absorption of dietary and biliary cholesterol. Concomitant use of pitavastatin did not affect the plasma concentrations of ezetimibe or its glucuronide metabolite, and ezetimibe did not affect the plasma concentrations of pitavastatin.

CYP3A4 isoenzyme inhibitors

Interaction studies with itraconazole and grapefruit juice, known inhibitors of the CYP3A4 isoenzyme, did not reveal a clinically significant effect on the plasma concentrations of pitavastatin.

Digoxin

A known substrate of P-glycoprotein (Pgp), does not interact with pitavastatin. No significant changes in the plasma concentrations of pitavastatin or digoxin were observed with concomitant use.

Warfarin

The steady-state pharmacokinetics and pharmacodynamics (INR [International Normalized Ratio] and PT [prothrombin time]) of warfarin in healthy volunteers were not altered when warfarin was co-administered with pitavastatin 4 mg daily. Nevertheless, as with other statins, PT and INR should be monitored in patients receiving warfarin when pitavastatin is added to therapy.

Pediatric patients

Drug interaction studies have been conducted only in adult patients. The extent of interaction for the pediatric population is unknown.

Storage Conditions

The drug should be stored at a temperature below 25°C (77°F) in the original cardboard packaging.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.