Pitavastatin Velpharm (Tablets) Instructions for Use

Marketing Authorization Holder

Velpharm-M, LLC (Russia)

Manufactured By

Velpharm, LLC (Russia)

Velpharm-M, LLC (Russia)

ATC Code

C10AA08 (Pitavastatin)

Active Substance

Pitavastatin (Rec.INN registered by WHO)

Dosage Forms

	Pitavastatin Velpharm	Film-coated tablets 1 mg
		Film-coated tablets 2 mg
		Film-coated tablets 4 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

	1 tab.
Pitavastatin (as pitavastatin calcium)	1 mg

10 pcs. – jars – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs (10 pcs.) – cardboard packs (100 pcs.) – By prescription
10 pcs. – blister packs (11 pcs.) – cardboard packs (110 pcs.) – By prescription
10 pcs. – blister packs (12 pcs.) – cardboard packs (120 pcs.) – By prescription
10 pcs. – blister packs (2 pcs.) – cardboard packs (20 pcs.) – By prescription
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blister packs (4 pcs.) – cardboard packs (40 pcs.) – By prescription
10 pcs. – blister packs (5 pcs.) – cardboard packs (50 pcs.) – By prescription
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blister packs (7 pcs.) – cardboard packs (70 pcs.) – By prescription
10 pcs. – blister packs (8 pcs.) – cardboard packs (80 pcs.) – By prescription
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – By prescription
100 pcs. – jars – cardboard packs (100 pcs.) – By prescription
110 pcs. – jars – cardboard packs (110 pcs.) – By prescription
120 pcs. – jars – cardboard packs (120 pcs.) – By prescription
14 pcs. – jars – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (3 pcs.) – cardboard packs (42 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
14 pcs. – blister packs (5 pcs.) – cardboard packs (70 pcs.) – By prescription
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – By prescription
14 pcs. – blister packs (7 pcs.) – cardboard packs (98 pcs.) – By prescription
20 pcs. – jars – cardboard packs (20 pcs.) – By prescription
21 pcs. – jars – cardboard packs (21 pcs.) – By prescription
28 pcs. – jars – cardboard packs (28 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
40 pcs. – jars – cardboard packs (40 pcs.) – By prescription
50 pcs. – jars – cardboard packs (50 pcs.) – By prescription
60 pcs. – jars – cardboard packs (60 pcs.) – By prescription
7 pcs. – jars – cardboard packs (7 pcs.) – By prescription
7 pcs. – blister packs – cardboard packs (7 pcs.) – By prescription
7 pcs. – blister packs (10 pcs.) – cardboard packs (70 pcs.) – By prescription
7 pcs. – blister packs (11 pcs.) – cardboard packs (77 pcs.) – By prescription
7 pcs. – blister packs (12 pcs.) – cardboard packs (84 pcs.) – By prescription
7 pcs. – blister packs (2 pcs.) – cardboard packs (14 pcs.) – By prescription
7 pcs. – blister packs (3 pcs.) – cardboard packs (21 pcs.) – By prescription
7 pcs. – blister packs (4 pcs.) – cardboard packs (28 pcs.) – By prescription
7 pcs. – blister packs (5 pcs.) – cardboard packs (35 pcs.) – By prescription
7 pcs. – blister packs (6 pcs.) – cardboard packs (42 pcs.) – By prescription
7 pcs. – blister packs (7 pcs.) – cardboard packs (49 pcs.) – By prescription
7 pcs. – blister packs (8 pcs.) – cardboard packs (56 pcs.) – By prescription
7 pcs. – blister packs (9 pcs.) – cardboard packs (63 pcs.) – By prescription
70 pcs. – jars – cardboard packs (70 pcs.) – By prescription
80 pcs. – jars – cardboard packs (80 pcs.) – By prescription
90 pcs. – jars – cardboard packs (90 pcs.) – By prescription

Film-coated tablets

	1 tab.
Pitavastatin (as pitavastatin calcium)	2 mg

Film-coated tablets

	1 tab.
Pitavastatin (as pitavastatin calcium)	4 mg

Pharmacotherapeutic Group

Hypolipidemic agents; HMG-CoA reductase inhibitors

Pharmacological Action

Pitavastatin is a competitive inhibitor of HMG-CoA reductase, the enzyme that catalyzes the initial stage of cholesterol synthesis – the conversion of HMG-CoA to mevalonic acid.

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 easily metabolized to acetyl-CoA, which is involved in many synthesis processes in the body.

Clinical studies have shown the effectiveness of pitavastatin in reducing plasma concentrations of total cholesterol (TC), LDL cholesterol (LDL-C), VLDL cholesterol, triglycerides (TG), and apolipoprotein B (Apo-B), as well as increasing the concentration of HDL cholesterol and apolipoprotein A1 (Apo-A1).

Pharmacokinetics

Pitavastatin is rapidly absorbed in the upper gastrointestinal tract, with C_max in plasma 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.

Unchanged Pitavastatin undergoes enterohepatic circulation and is well absorbed from the jejunum and ileum.

The absolute bioavailability of pitavastatin is 51%.

More than 99% of pitavastatin binds to plasma proteins, mainly albumin and alpha-1 acid glycoprotein.

The mean V_d is 133 L.

Pitavastatin actively penetrates hepatocytes via the 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.

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 affects 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.

Pitavastatin in unchanged form is rapidly excreted 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.

The T_1/2 from plasma varies from 5.7 hours (single dose) to 8.9 hours (at steady state), with a mean clearance value of 43.4 L/h after a single oral dose.

Indications

Primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson type IIa hyperlipidemia) or mixed hypercholesterolemia (Fredrickson type IIb hyperlipidemia), hypertriglyceridemia (Fredrickson type IV hyperlipidemia) as an adjunct to diet, when diet and other non-pharmacological treatments (e.g., exercise, weight loss) are insufficient.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
E78.0	Pure hypercholesterolemia
E78.1	Pure hyperglyceridemia
E78.2	Mixed hyperlipidemia

ICD-11 code	Indication
5C80.00	Primary hypercholesterolemia
5C80.1	Hypertriglyceridemia
5C80.2	Mixed hyperlipidemia
EB90.21	Tuberous xanthoma
EB90.22	Eruptive xanthoma

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Orally. The initial dose is 1 mg once/day. If necessary, the dose can be increased at intervals of at least 4 weeks to 2 mg/day. The dose should be individually selected in accordance with LDL-C concentrations, treatment goals, and the patient’s response to therapy. For most patients, a dose of 2 mg is required. The maximum daily dose is 4 mg.

Patients with mild to moderate hepatic impairment: the recommended maximum daily dose is 2 mg.

Patients with renal impairment: In mild renal impairment (it is advisable to objectively assess this degree with reflection of CrCl or GFR), Pitavastatin should be used with caution. Data on the use of the maximum daily dose of 4 mg in any degree of renal impairment are limited, therefore, prescribing the maximum daily dose of 4 mg should only be done with careful monitoring of renal function after gradual dose escalation. 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.

Adverse Reactions

Hematopoietic system uncommon – anemia.

Metabolism uncommon – anorexia.

Nervous system common – headache, insomnia; uncommon – dizziness, taste disturbance, drowsiness.

Sensory organs: uncommon – tinnitus; rare – decreased visual acuity.

Skin: uncommon – pruritus, rash; rare – urticaria, erythema.

Musculoskeletal system common – myalgia, arthralgia; uncommon – muscle spasms; rare – myopathy, rhabdomyolysis; frequency unknown – occurrence or exacerbation of myasthenia.

Urinary system: uncommon – pollakiuria.

Digestive system common – constipation, diarrhea, dyspepsia, nausea; uncommon – abdominal pain, dry mouth, vomiting; rare – glossodynia, acute pancreatitis, liver dysfunction, cholestatic jaundice.

Organ of vision frequency unknown – ocular myasthenia.

Laboratory parameters uncommon – increased activity of “liver” transaminases AST, ALT, increased CPK activity.

Other uncommon – asthenia, malaise, increased fatigue, peripheral edema.

Contraindications

Severe hepatic insufficiency (more than 9 points on the Child-Pugh scale) or class C according to the Child-Pugh classification, active liver disease, including persistent increase in serum liver transaminase activity (more than 3 times the ULN); myopathy; concomitant use of cyclosporine; pregnancy, breastfeeding period, lack of adequate contraceptive methods in women of childbearing potential; age under 18 years (efficacy and safety not established); hypersensitivity to pitavastatin and other HMG-CoA reductase inhibitors (statins).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

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

The use of the drug is contraindicated in severe hepatic insufficiency (more than 9 points on the Child-Pugh scale) or Child-Pugh class C, active liver disease, including persistent elevation of serum hepatic transaminases (more than 3 times the upper limit of normal).

Use in Renal Impairment

The drug should be used with caution in renal failure. Data on the use of the maximum daily dose of 4 mg in renal impairment of any severity are limited; therefore, the maximum daily dose of 4 mg should be prescribed only with careful monitoring of renal function after gradual dose titration. 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.

Pediatric Use

The use of the drug is contraindicated in patients under 18 years of age (because efficacy and safety have not been established).

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

Use with caution in the presence of risk factors for myopathy/rhabdomyolysis – renal failure, hypothyroidism, personal or family history of hereditary muscular diseases, and previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates, excessive alcohol consumption, age over 70 years, history of liver disease.

Patients should be advised to report any muscle symptoms. Creatine phosphokinase activity should be measured in any patient reporting muscle pain, muscle tenderness on palpation, or weakness, especially if accompanied by malaise or fever.

Creatine phosphokinase levels should not be measured after physical exertion or in the presence of any other possible causes of elevated creatine phosphokinase that may distort the result. If creatine phosphokinase activity is elevated (5 times above the upper limit of normal), a confirmatory test should be performed within 5-7 days.

Use with caution in patients with predisposing factors for the development of rhabdomyolysis. Creatine phosphokinase activity should be measured to establish a baseline reference value in the following cases: renal failure; hypothyroidism; personal or family history of hereditary muscular diseases; previous history of muscle toxicity during treatment with fibrates or other statins; history of liver disease or alcohol abuse; elderly patients (over 70 years) 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 should not be initiated if creatine phosphokinase levels are 5 times the upper limit of normal.

The patient should be advised to immediately inform the doctor of any muscle pain, weakness, or cramps. Creatine phosphokinase activity should be measured, and treatment discontinued if creatine phosphokinase activity is elevated (5 times above the upper limit of normal). Discontinuation of treatment should be considered if severe muscle symptoms occur, even if creatine phosphokinase levels do not exceed 5 times the upper limit of normal. If symptoms resolve and creatine phosphokinase activity returns to normal, re-initiation of therapy at a dose of 1 mg with careful monitoring may be considered.

As with all statins, Pitavastatin should be used with caution in patients with a history of liver disease, or in patients who regularly consume excessive amounts of alcohol. Liver function tests should be performed before initiating treatment with pitavastatin and periodically during treatment. Treatment with pitavastatin should be discontinued in patients with persistent elevation of hepatic transaminases (ALT and AST), exceeding 3 times the upper limit of normal.

Use with caution in patients with moderate or severe renal failure. Dose titration should only be performed under careful monitoring. The 4 mg dose is not recommended for patients with severe renal failure.

Some evidence suggests that statins, as a class, cause an increase in blood glucose levels, and in some patients at high risk of developing diabetes mellitus, may lead to a level of hyperglycemia requiring appropriate antidiabetic therapy. However, this risk is offset by the reduction in vascular risk with statin treatment, and therefore should not be a reason for discontinuing statin therapy. Patients at risk of developing hyperglycemia (fasting glucose from 5.6 to 6.9 mmol/L, BMI>30 kg/m², elevated TG concentration, arterial hypertension) should undergo clinical and biochemical monitoring in accordance with national guidelines.

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.

Effect on Driving and Operating Machinery

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

Drug Interactions

Pitavastatin is actively transported into the human hepatocyte 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. 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), Pitavastatin should be used with caution.

Fusidic acid: Severe muscle disorders, such as rhabdomyolysis, attributed to an interaction between fusidic acid and statins have been reported. During treatment with fusidic acid, temporary discontinuation of pitavastatin is recommended.

Rifampicin: Concomitant administration with pitavastatin resulted in a 1.3-fold increase in the AUC of pitavastatin.

Ezetimibe and its glucuronide metabolite inhibit the absorption of dietary and biliary cholesterol. Concomitant use with pitavastatin 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 interaction 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 during concomitant use.

Warfarin: The steady-state pharmacokinetics and pharmacodynamics (INR and prothrombin time) of warfarin in healthy volunteers were not altered when warfarin was co-administered with pitavastatin 4 mg daily. However, as with other statins, in patients receiving warfarin, prothrombin time and INR should be monitored when pitavastatin is added to the therapy.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.

Medical Disclaimer

Medixlife (Author)

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