Livazo 4mg 28 tablets

Form

tableti saghech i

Dosage mg

4

Pack

28

Trade Name: Livazo International Nonproprietary Name: Pitavastatin Dosage Form: Film-coated tablets Composition of one tablet: 1mg 2mg 4mg Active substance: Pitavastatin calcium 1.045mg 2.090mg 4.180mg (equivalent to Pitavastatin) (1.000mg) (2.000mg) (4.000mg) Excipients: Lactose monohydrate 63.085mg 126.170mg 252.340mg Low-substituted hydroxypropyl cellulose 12.540mg 25.080mg 50.160mg Hypromellose 1.330mg 2.660mg 5.320mg Magnesium aluminometasilicate 1.600mg 3.200mg 6.400mg Magnesium stearate 0.400mg 0.800mg 1.600mg Film coating: Opadry White1 3.000mg 5.000mg 9.000mg 1Composition of Opadry White: Hypromellose 1.9800mg 3.3065mg 5.9520mg Titanium dioxide 0.8000mg 1.3380mg 2.4090mg Triethyl citrate 0.2000mg 0.3305mg 0.5940mg Colloidal silicon dioxide 0.0200mg 0.0250mg 0.0450mg Description: Round, biconvex, white film-coated tablets. The core is white in cross-section. One side of the tablet is imprinted with "KS", and the other side with "1", "2", or "4" according to the dosage. Pharmacotherapeutic group: Antihyperlipidemic agent - HMG-CoA reductase inhibitor. ATC CODE: C10AA08 See blog: Livazo - A Modern Solution for Cholesterol Management Pharmacological Properties Pharmacodynamics: Pitavastatin is a competitive inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme that catalyzes the initial step of cholesterol synthesis – the conversion of HMG-CoA to mevalonic acid. Since the conversion of HMG-CoA to mevalonic acid is the initial step in cholesterol synthesis, pitavastatin intake does not lead to the accumulation of potentially toxic sterols in the body. HMG-CoA is readily metabolized to acetyl-CoA, which participates in many synthetic processes in the body. Clinical studies have demonstrated the efficacy of Livazo in reducing plasma concentrations of 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) concentrations (see Table 1). Table 1. Dose-Response in Patients with Primary Hypercholesterolemia (Adjusted Mean Percentage Change from Baseline) Dose N LDL-C TC* HDL-C TG Apo-B Apo-A1 Placebo 51 -4.0 -1.3 2.5 -2.1 0.3 3.2 1mg 52 -33.3 -22.8 9.4 -14.8 -24.1 8.5 2mg 49 -38.2 -26.1 9.0 -17.4 -30.4 5.6 4mg 50 -46.5 -32.5 8.3 -21.2 -36.1 4.7 In patients who underwent percutaneous coronary intervention for acute coronary syndrome, ultrasound examination of the vessels showed that 4mg of pitavastatin administered for 8-12 months reduced coronary plaque volume by approximately 17% and was accompanied by regression of vascular remodeling (from 113.0 to 105.4 mm3). The desired effects in terms of mortality and complications have not yet been evaluated. Diabetes Mellitus: In patients with hyperlipidemia and impaired glucose tolerance, along with lifestyle modifications, treatment with Livazo at doses of 1mg/day or 2mg/day resulted in a lower incidence of new-onset diabetes mellitus compared to patients not receiving lipid-lowering therapy: 39.9% vs 45.7% over 2.8 years, with a hazard ratio of 0.82. In terms of diabetes mellitus risk, this meta-analysis of pitavastatin safety showed a neutral effect of Livazo on the development of new cases of diabetes mellitus compared to treatment with other statins. Pharmacokinetics Absorption: Pitavastatin is rapidly absorbed in the upper gastrointestinal tract, with peak plasma concentration (Cmax) achieved within 1 hour after administration. Food does not affect absorption. Cmax of pitavastatin in plasma decreases by 43% when taken with fatty food, but the area under the concentration-time curve (AUC) remains unchanged. The unchanged drug undergoes enterohepatic circulation and is well absorbed from the jejunum and ileum. The absolute bioavailability of pitavastatin is 51%. Distribution: More than 99% of pitavastatin is bound to plasma proteins, mainly albumin and alpha-1-acid glycoprotein. The mean volume of distribution is 133 L. Pitavastatin actively enters hepatocytes via transporter proteins OATP1B1 and OATP1B3. AUC varies within a four-fold range from minimum to maximum values. Pitavastatin is not a substrate for P-glycoprotein. Elimination: Unchanged pitavastatin is rapidly eliminated from the liver via bile but undergoes enterohepatic recirculation, ensuring its prolonged effect. Less than 5% of pitavastatin is excreted by the kidneys. The plasma half-life ranges from 5.7 hours (single dose) to 8.9 hours (steady state), with a mean clearance of 43.4 L/h after a single oral dose. Pharmacokinetics in Different Patient Groups: Elderly: In patients over 65 years of age, the AUC of pitavastatin was 1.3 times higher. This factor did not affect the efficacy or safety of the drug. Hepatic Impairment: In patients with mild hepatic impairment (Child-Pugh Class A), AUC was 1.6 times higher than in healthy volunteers, and in patients with moderate hepatic impairment (Child-Pugh Class B), AUC was 3.9 times higher. Pitavastatin is contraindicated in patients with severe hepatic impairment. Renal Impairment: In patients with moderate renal impairment and those on hemodialysis, AUC increased by 1.8-fold and 1.7-fold, respectively. Sex Differences: In a study in healthy volunteers, AUC was 1.6 times higher in women compared to men, which did not affect the efficacy and safety of Livazo. Race: According to pharmacokinetic analysis of data from healthy volunteers of different races (Japanese or Caucasian populations), factors such as sex and age do not affect the pharmacokinetics of pitavastatin. Indications for Use: 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 alone and other non-drug treatment methods (e.g., exercise, weight reduction) are insufficient. Contraindications: Hypersensitivity to pitavastatin, excipients of the drug, and other HMG-CoA reductase inhibitors (statins). Severe (Child-Pugh score > 9) or Class C hepatic impairment according to Child-Pugh classification, active liver disease, including elevated serum liver transaminases (more than 3 times the upper limit of normal). Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption. Myopathy. Concomitant use of cyclosporine. Pregnancy, breastfeeding, and in women of childbearing potential without adequate contraception. Age under 18 years (efficacy and safety not established). Precautions: When there is a risk of developing myopathy/rhabdomyolysis, renal impairment, hypothyroidism, personal or family history of hereditary muscle diseases, and a history of muscle-related toxicity from previous use of other HMG-CoA reductase inhibitors or fibrates, liver disease in history, excessive alcohol consumption, age over 70 years. Drug Use During Pregnancy and Breastfeeding: Pregnancy: Livazo is contraindicated during pregnancy. Women of childbearing potential should use reliable methods of contraception during treatment with Livazo. Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs the benefits of the drug during pregnancy. Animal studies have shown reproductive toxicity of pitavastatin, although without teratogenic potential. If a patient plans to become pregnant, the drug should be discontinued at least one month before conception. If pregnancy occurs during treatment with Livazo, treatment should be stopped immediately. Breastfeeding: Livazo is contraindicated during breastfeeding. Pitavastatin is excreted in rat milk. There is no data on the transfer of pitavastatin into human milk. If Livazo is necessary during lactation, breastfeeding should be discontinued. Dosage and Administration: Administer orally, swallow the tablet whole. It is preferable to take the tablets at the same time each day, preferably in the evening, in accordance with the circadian rhythm of lipid metabolism. Before starting treatment and during treatment, the patient should follow a hypocholesterolemic diet. The initial dose of the drug is 1mg once daily. If necessary, the dose can be increased to 2mg daily at intervals of at least 4 weeks. The dose should be individualized based on LDL-C concentrations, treatment goals, and patient response to treatment. Most patients require a dose of 2mg. The maximum daily dose is 4mg. Patients with mild to moderate hepatic impairment: The recommended maximum daily dose is 2mg. Patients with renal impairment: In patients with mild renal impairment (objective assessment of renal function severity based on creatinine clearance or glomerular filtration rate is recommended), Livazo should be used with caution. Data on the use of the maximum daily dose of 4mg in patients with any degree of renal impairment are limited; therefore, the maximum daily dose of 4mg should be prescribed only if renal function is carefully monitored after gradual dose escalation. In patients with severe renal impairment, the maximum daily dose of 4mg is not recommended; in severe renal failure, it is advisable to limit the maximum dose to 2mg. Elderly patients: Dose adjustment is not required. Adverse Reactions: In controlled clinical trials, less than 4% of patients treated with Livazo discontinued the study due to adverse reactions. Myalgia was the most frequently reported. Adverse reactions are classified by frequency according to the World Health Organization classification: Very common: ≥10% Common: ≥1/100 to <1/10 Uncommon: ≥1/1000 to <1/100 Rare: ≥1/10000 to <1/1000 Very rare: <1/10000 Frequency not known (frequency cannot be estimated from available data). Blood and lymphatic system disorders: Uncommon: Anemia Metabolism and nutrition disorders: Uncommon: Anorexia Psychiatric disorders: Common: Insomnia Nervous system disorders: Common: Headache Uncommon: Dizziness, taste disturbance, somnolence Sensory organ and special senses disorders: Uncommon: Tinnitus Rare: Decreased visual acuity Skin and subcutaneous tissue disorders: Uncommon: Pruritus, rash Rare: Urticaria, erythema Musculoskeletal and connective tissue disorders: Common: Myalgia, arthralgia Uncommon: Muscle spasms Frequency not known: Immune-mediated necrotizing myopathy Urinary system disorders: Uncommon: Pollakiuria Gastrointestinal disorders: Common: Constipation, diarrhea, dyspepsia, nausea Uncommon: Abdominal pain, dry mouth, vomiting Rare: Glossodynia, acute pancreatitis, cholestatic jaundice Laboratory findings: Uncommon: Increased activity of liver transaminases - aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase (CPK). In clinical trials, CPK activity increased by 3 times the upper limit of normal in 2800 out of 49 patients (1.8%) after Livazo administration. An increase of ≥10 times the upper limit of normal with muscle-related concomitant symptoms was very rare, occurring in only one patient out of 2406 who received 4mg of Livazo (0.04%) within the clinical trial program. Other disorders: Uncommon: Asthenia, weakness, fatigue, peripheral edema. Post-marketing Experience: A two-year prospective post-marketing surveillance study was conducted in Japan with approximately 20,000 patients. Most of these patients received pitavastatin at a dose of 1 or 2 mg, but not 4 mg. Adverse reactions, for which a causal relationship with pitavastatin cannot be excluded, were observed in 10.4% of patients, and 7.4% of patients discontinued treatment due to adverse reactions. The incidence of myalgia was 1.08%. Most adverse reactions were mild. Over 2 years, adverse reactions were more frequent in patients with a history of drug allergy (20.4%) or liver or kidney disease (13.5%). Adverse reactions and their incidence observed with recommended doses of the drug in the post-marketing prospective study, not in international controlled clinical trials, are listed below. Hepatobiliary disorders: Rare: Hepatic dysfunction, liver disease Musculoskeletal and connective tissue disorders: Rare: Myopathy, rhabdomyolysis. In the post-marketing surveillance study, two cases of rhabdomyolysis requiring hospitalization were reported (0.01% of patients). Additionally, there are spontaneous reports of musculoskeletal effects, including myalgia and myopathy, in patients taking recommended doses of Livazo. Cases of rhabdomyolysis with and without acute renal failure have also been reported, including fatal rhabdomyolysis. Spontaneous reports of the following adverse reactions have also been received (their frequency is based on cases reported in post-marketing studies): Nervous system disorders: Uncommon: Hypoesthesia Gastrointestinal disorders: Rare: Abdominal discomfort Adverse reactions observed with other statins: - Sleep disturbances, including nightmares; - Amnesia; - Sexual dysfunction; - Depression; - Interstitial lung disease; - Diabetes mellitus: incidence depends on the presence or absence of risk factors (fasting glucose concentration ≥5.6 mmol/L, body mass index >30 kg/m2, elevated TG concentration, history of arterial hypertension); - Increased glycosylated hemoglobin. Overdose: There is no specific treatment for overdose. Symptomatic treatment should be provided, and CPK activity and liver function should be monitored. Hemodialysis is ineffective. Drug Interactions: Pitavastatin is actively transported into human hepatocytes via numerous hepatic transporters (including organic anion transporting polypeptide [OATP]), which may be involved in the interaction of some of these drugs. Cyclosporine: Co-administration of single doses of cyclosporine with pitavastatin resulted in a 4.6-fold increase in pitavastatin AUC at steady state. The effect of cyclosporine steady state on pitavastatin steady state is unknown. Livazo is contraindicated in patients taking cyclosporine. Erythromycin: Co-administration of erythromycin and pitavastatin resulted in a 2.8-fold increase in pitavastatin AUC. Temporary discontinuation of pitavastatin is recommended during treatment with erythromycin or other macrolide antibiotics. Gemfibrozil and other fibrates: Fibrate monotherapy is rarely associated with the development of myopathy. Concomitant use of statins with fibrates increases the incidence of myopathy and rhabdomyolysis. Pitavastatin should be used with caution with fibrates. In studies of combined administration of pitavastatin and gemfibrozil, a 1.4-fold increase in pitavastatin AUC and a 1.2-fold increase in fenofibrate AUC were observed. Nicotinic acid (in hypolipidemic doses): A study of the interaction between pitavastatin and hypolipidemic doses of nicotinic acid (>1g/day) has not been conducted. Nicotinic acid monotherapy is associated with the development of myopathy and rhabdomyolysis. Therefore, concomitant use of hypolipidemic doses of nicotinic acid (>1 g/day) and Livazo should be prescribed with caution. Fusidic acid: Acute muscle-related disorders such as rhabdomyolysis have been reported due to the interaction of fusidic acid and statins. Temporary discontinuation of Livazo is recommended during treatment with fusidic acid. Rifampicin: Co-administration with pitavastatin increased pitavastatin AUC by 1.3-fold, due to reduced accumulation in the liver. HIV protease inhibitors: Co-administration with pitavastatin caused minor changes in pitavastatin AUC. Ezetimibe and its glucuronide metabolite inhibit the absorption of dietary and biliary cholesterol. In combined use, pitavastatin did not affect plasma concentrations of ezetimibe or its glucuronide metabolite, and ezetimibe did not affect pitavastatin plasma concentrations. Special Precautions: Effects on Muscle Tissue: As with other HMG-CoA reductase inhibitors (statins), there is a possibility of developing myalgia, myopathy, and rarely rhabdomyolysis. Patients should be advised to report any muscle-related symptoms immediately. When a patient experiences muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever, CPK activity should be determined. CPK activity determination should not be performed after physical exertion or in the presence of other factors that cause CPK elevation, as the result may be misleading. If CPK activity is elevated (more than 5 times the upper limit of normal), a control analysis should be performed within 5-7 days. Very rare cases of immune-mediated necrotizing myopathy have been reported during or after statin treatment. Immune-mediated necrotizing myopathy is clinically characterized by chronic proximal muscle weakness and elevated serum CPK activity that persists despite statin discontinuation. Before treatment, like other statins, Livazo should be prescribed with caution in patients with risk factors that predispose to rhabdomyolysis. CPK activity should be determined to establish baseline control values in the following cases: renal impairment, hypothyroidism, personal or family history of hereditary muscle diseases, history of muscle-related toxicity from previous treatment with fibrates or other statins, history of liver disease or excessive alcohol consumption, patients over 70 years of age with other risk factors predisposing to rhabdomyolysis. In such cases, clinical monitoring is recommended, and the risk-benefit ratio of treatment should be reviewed. Livazo should not be taken if CPK activity exceeds 5 times the upper limit of normal. During treatment, patients should be advised to notify their doctor immediately if they experience muscle pain, weakness, or cramps. CPK activity should be determined, and treatment should be discontinued if it is elevated (more than 5 times the upper limit of normal). In case of acute muscle-related symptoms, the decision to discontinue treatment should be reconsidered even if CPK activity does not exceed 5 times the upper limit of normal. After resolution of symptoms and normalization of CPK activity, Livazo may be re-administered at a dose of 1mg under regular monitoring. Effects on the Liver: Like other statins, Livazo should be prescribed 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 and periodically during treatment. If the activity of liver transaminases (ALT and AST) increases and exceeds 3 times the upper limit of normal, Livazo intake should be discontinued. Effects on the Kidneys: Livazo should be prescribed with caution in patients with moderate or severe renal impairment. Dose increases are permissible only under regular monitoring. A dose of 4mg is not recommended in patients with severe renal impairment. Diabetes Mellitus: Some data suggest that statins can increase blood glucose concentrations, increasing the risk of diabetes mellitus, and in some patients with a high risk of developing diabetes mellitus, it may cause hyperglycemia and require appropriate diabetes treatment. Nevertheless, this risk is compensated by the reduction in cardiovascular risks associated with statin treatment, and therefore should not be a reason to discontinue statins. In patients with risk factors for hyperglycemia (fasting glucose concentration 5.6-6.9 mmol/L, body mass index >30 kg/m2, elevated TG concentration, arterial hypertension), clinical and biochemical monitoring is required according to national recommendations. At the same time, according to post-marketing surveillance and prospective studies, no confirmed signs of increased diabetes mellitus risk have been observed during pitavastatin treatment. Interstitial Lung Disease: Rare cases of interstitial lung disease have been reported with some statins, especially with long-term treatment. Clinical signs include dyspnea, non-productive cough, and general deterioration of health (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin intake should be discontinued. Effect on Ability to Drive and Use Machinery: Caution should be exercised when driving or operating machinery that requires maximum attention, as adverse reactions such as dizziness and somnolence may occur. Dosage Form: Film-coated tablets 1mg, 2mg, and 4mg. 1mg dose: 7, 14, 15 tablets in Al/PVC blisters, 1 or 2 blisters are placed in a cardboard box with instructions for use. 2mg dose: 7, 10, 14, 15, 20 tablets in Al/PVC blisters, 1, 2, 3, or 5 blisters are placed in a cardboard box with instructions for use. 4mg dose: 7, 10, 14, 15 tablets in Al/PVC blisters, 1, 2, or 3 blisters are placed in a cardboard box with instructions for use. Storage Conditions: Store in a protected place from light, at a temperature not exceeding 25°C, out of reach of children. Shelf Life: 4 years. Do not use after the expiry date. Dispensing Regime: Pharmaceutical product group - II, dispensed with prescription form №3.