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Питавастатин конкурентно ингибирует ГМГ-КоА-редуктазу, ограничивая скорость действия фермента в биосинтезе холестерина, ингибирует синтез холестерина (Хс) в печени. Вследствие этого экспрессия рецепторов ЛПНП в печени повышается, способствуя захвату циркулирующих ЛПНП в крови, снижению общего Хс и холестерина ЛПНП (Хс-ЛПНП) в крови. Его стойкое ингибирование печеночного синтеза Хс снижает секрецию ЛПНП в кровь, снижая уровень триглицеридов в плазме крови. Ливазо снижает повышенный уровень Хс-ЛПНП, общего Хс и триглицеридов, и повышает уровень холестерина ЛПВП (Хс-ЛПВП). Препарат снижает уровень аполипопротеинов (Апо-B) и приводит к вариабельному увеличению Апо-А1. Фармакокинетика Всасывание Питавастатин быстро всасывается в верхних отделах ЖКТ, Cmax в плазме крови достигается на протяжении 1 ч после приема внутрь. Всасывание не зависит от приема пищи. Препарат в неизмененном виде проходит энтерогепатическую циркуляцию и хорошо всасывается в тонком кишечнике. Абсолютная биодоступность питавастатина составляет 51%. Cmax питавастатина в плазме крови снижалась на 43% при приеме пищи с высоким содержанием жиров, но AUC оставалась неизмененной. Распределение Питавастатин более чем на 99% связывается с белками плазмы крови, в основном с альбумином и α1-кислотным глюкопротеином, средний Vd составляет около 133 л. Питавастатин активно транспортируется в гепатоциты, место действия и метаболизма, многими печеночными носителями, в том числе ОATP1B1 и OATP1B3. AUC в плазме изменяется с приблизительно 4-кратным диапазоном между наивысшими и наиболее низкими значениями. Исследования по SLCO1B1 (ген, который кодирует OATP1B1) дают возможность предположить, что полиморфизм данного гена может объяснить большое колебание AUC. Питавастатин не является субстратом для Р-глюкопротеина. Метаболизм Питавастатин в неизмененном виде является большей частью препарата в плазме крови. Основной метаболит - неактивный лактон, который формируется через конъюгат глюкуронида питавастатина эфирного типа UDP глюкуронозилтрансферазой (UGT1A3 и 2B7). Исследования in vitro с использованием 13 изоформ человеческого цитохрома P450 (CYP) показывают, что метаболизм питавастатина с помощью CYP является минимальным; CYP2C9 (и в меньшей степени CYP2C8) отвечает за метаболизм питавастатина до незначительных метаболитов. Выведение Питавастатин в неизмененном виде быстро выводится из печени в желчь, но подвергается энтерогепатической рециркуляции, что предопределяет продолжительность его действия. Менее 5% питавастатина выводится с мочой. T1/2 из плазмы крови колеблется от 5.7 ч (1 доза) до 8.9 ч (равновесное состояние), среднее геометрическое перорального клиренса составляет 43.4 л/ч после одноразовой дозы.

Активное вещество: питавастатин кальция 2.09, что соответствует содержанию питавастатина 2 мг, Вспомогательные вещества: лактозы моногидрат - 126.17 мг, гипролоза низкозамещенная - 25.08 мг, гипромеллоза - 2.66 мг, магния алюмометасиликат - 3.2 мг, магния стеарат - 0.8 мг.

Первичная гиперхолестеринемия, включая гетерозиготную семейную гиперхолестеринемию (гиперлипидемия IIа типа по классификации Фредриксона) или смешанная гиперхолестеринемия(гиперлипидемия IIb типа по классификации Фредриксона) гипертриглицеридемия (гиперлипидемия IV типа но классификации Фредриксона) в качестве дополнения к диете, когда диета и другие немедикаментозные методы лечения (например, физические упражнения, снижение массы тела) оказываются недостаточными.

Повышенная чувствительность к питавастатину, вспомогательным компонентам препарата и другим ингибиторам ГМГ-КоА-редуктазы (статинам); тяжелая печеночная недостаточность (более 9 баллов по шкале Чайлд-Пью) или класс С по классификации Чайлд-Пью, заболевания печени и активной фазе, включая стойкое повышение активности печеночных трансаминаз в сыворотке крови (более чем в 3 раза по сравнению с ВГН); миопатия; одновременный прием циклоспорина; беременность; период грудного вскармливания; отсутствие адекватных методов контрацепции у женщин детородного возраста; возраст до 18 лет (эффективность и безопасность не установлены). непереносимость лактозы, дефицит лактазы или глюкозо-галактозная мальабсорбция.

Summary of the safety profile In controlled clinical trials, at the recommended doses, less than 4% of Livazo treated patients were withdrawn due to adverse events. The most commonly reported pitavastatin related adverse reaction in controlled clinical trials was myalgia. Summary of adverse reactions Adverse reactions and frequencies observed in worldwide controlled clinical trials and extension studies, at the recommended doses, are listed below by system organ class. Frequencies are defined as: very common (≥1/10), common (≥1/100, to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000) and not known. Blood and the lymphatic system disorders Uncommon: Anaemia Metabolism and nutrition disorders Uncommon: Anorexia  Psychiatric disorders Uncommon: Insomnia Nervous system disorders Common: Headache Uncommon: Dizziness, Dysgeusia, Somnolence Eye disorders Rare: Visual acuity reduced Ear and labyrinth disorders Uncommon: Tinnitus Gastrointestinal disorders Common: Constipation, Diarrhoea, Dyspepsia, Nausea Uncommon: Abdominal Pain, Dry Mouth, Vomiting Rare: Glossodynia, pancreatitis acute Hepato-biliary disorders Uncommon: Transaminases (aspartate aminotransferase, alanine aminotransferase) increased Rare: Jaundice cholestatic Skin and subcutaneous tissue disorders Uncommon: Pruritus, Rash Rare: Urticaria, Erythema Musculoskeletal, connective tissue and bone disorders Common: Myalgia, Arthralgia Uncommon: Muscle spasms Frequency unknown: Immune-mediated necrotising myopathy  Renal and urinary disorders Uncommon: Pollakiuria  General disorders and administration site conditions Uncommon: Asthenia, Malaise, Fatigue, Peripheral Oedema Elevated blood creatinine kinase of >3 times the upper limit of normal (ULN) occurred in 49 out of 2800 (1.8%) patients receiving Livazo in the controlled clinical trials. Levels of ≥10 times ULN with concurrent muscle symptoms were rare and only observed in one patient out of 2406 treated with 4mg Livazo (0.04%) in the clinical trial programme. Paediatric population The clinical safety database includes safety data for 142 paediatric patients who received pitavastatin among which 87 patients were in the age range of 6 to 11, and 55 patients were in the age range of 12 to 17. In total, 91 patients received pitavastatin for 1 year with 12 patients receiving pitavastatin for 2.5 years and 2 patients for 3 years. Less than 3% of pitavastatin treated patients were withdrawn due to adverse events. The most commonly reported pitavastatin related adverse reactions in the clinical programme were headache (4.9%), myalgia (2.1%) and abdominal pain (4.9%). Based on the data available, the frequency, type and severity of adverse reactions are expected to be similar in children and adolescents to adults. Post Marketing Experience A two year prospective post-marketing surveillance study was conducted in nearly 20,000 patients in Japan. The overwhelming majority of the 20,000 patients in the study were treated with 1mg or 2mg pitavastatin and not 4mg. 10.4% of patients reported adverse events for which a causal relationship to pitavastatin could not be ruled out and 7.4% of patients withdrew from therapy due to adverse events.  The myalgia rate was 1.08%. The majority of adverse events were mild. Adverse event rates were higher over 2 years in patients with a history of drug allergy (20.4%), or hepatic or renal disease (13.5%). Adverse reactions and frequencies observed in the prospective post-marketing surveillance study but not in worldwide controlled clinical trials, at the recommended doses are listed below.  Hepato-biliary disorders Rare: Hepatic function abnormal, Liver disorder Musculoskeletal, connective tissue disorders Rare: Myopathy, Rhabdomyolysis In the post-marketing surveillance study there were two reports of rhabdomyolysis requiring hospitalisation (0.01% of patients). In addition there are unsolicited post-marketing reports of skeletal muscle effects including myalgia and myopathy in Livazo treated patients at all recommended doses. Reports of rhabdomyolysis, with and without acute renal failure, including fatal rhabdomyolysis have also been received. Unsolicited reports of the following events have also been received (the frequency is based on that observed in post-marketing studies): Nervous system disorders Uncommon: Hypoaesthesia Gastrointestinal disorders Rare: Abdominal discomfort Statin class effects The following adverse events have been reported with some statins: Sleep disturbances, including nightmares Memory loss Sexual dysfunction Depression Exceptional cases of interstitial lung disease, especially with long term therapy  Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI >30 kg/m2  raised triglycerides, history of hypertension)

Pitavastatin is actively transported into human hepatocytes by multiple hepatic transporters (including organic anion transporting polypeptide, OATP), which may be involved in some of the following interactions. Ciclosporin: Co-administration of a single dose of ciclosporin with Livazo at steady state resulted in a 4.6-fold increase in pitavastatin AUC. The effect of steady state ciclosporin on steady state Livazo is not known. Livazo is contraindicated in patients being treated with ciclosporin. Erythromycin: Co-administration with Livazo resulted in a 2.8-fold increase in pitavastatin AUC. A temporary suspension of Livazo is recommended for the duration of treatment with erythromycin or other macrolide antibiotics. Gemfibrozil and other fibrates: The use of fibrates alone is occasionally associated with myopathy. Co-administration of fibrates with statins has been associated with increased myopathy and rhabdomyolysis. Livazo should be administered with caution when used concomitantly with fibrates. In Pharmacokinetic studies co-administration of Livazo with Gemfibrozil resulted in a 1.4-fold increase in pitavastatin AUC; with Fenofibrate AUC, increased 1.2-fold. Niacin: Interaction studies with Livazo and niacin have not been conducted. The use of niacin alone has been associated with myopathy and rhabdomyolysis when used as a monotherapy. Thus Livazo should be administered with caution when used concomitantly with niacin. Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with systemic fusidic acid is necessary, Livazo treatment should be discontinued throughout the duration of the fusidic acid treatment Rifampicin: Co-administration with Livazo at the same time resulted in a 1.3-fold increase in pitavastatin AUC due to reduced hepatic uptake. Protease inhibitors: Co-administration with Livazo at the same time may result in minor changes in pitavastatin AUC. Ezetimibe and its glucuronide metabolite inhibit the absorption of dietary and biliary cholesterol. Coadministration of Livazo had no effect on plasma ezetimibe or the glucuronide metabolite concentrations and ezetimibe had no impact on pitavastatin plasma concentrations. Inhibitors of CYP3A4: Interaction studies with itraconazole and grapefruit juice, known inhibitors of CYP3A4, had no clinically significant effect on the plasma concentrations of pitavastatin. Digoxin, a known P-gp substrate, did not interact with Livazo. During co-administration there was no significant change in either pitavastatin or digoxin concentrations. Warfarin: The steady-state pharmacokinetics and pharmacodynamics (INR and PT) of warfarin in healthy volunteers was unaffected by the co-administration of Livazo 4mg daily. However, as for other statins, patients receiving warfarin should have their prothrombin time or INR monitored when Livazo is added to their therapy. Paediatric population Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.

При передозировке возможно усиление симптомов побочных реакций. Специфического антидота нет. Симптоматическое лечение и поддерживающие меры следует проводить по мере необходимости. Показатели функции печени и уровень креатинкиназы необходимо контролировать. Гемодиализ неэффективен.

Posology Patients should be on a cholesterol lowering diet before treatment. It is important that all patients continue dietary control during treatment. The usual starting dose is 1mg once daily. Adjustment of dose should be made at intervals of 4 weeks or more. Doses should be individualized according to LDL-C levels, the goal of therapy and patient response. The maximum daily dose is 4mg. Elderly No dose adjustment necessary in patients older than 70 years (see section 5.1 and Section 5.2). Paediatric population Children and adolescents aged 6 years and over: Livazo use in children should only be carried out by physicians experienced in the treatment of hyperlipidaemia and progress should be regularly reviewed. In children and adolescents with heterozygous familial hypercholesterolaemia the usual starting dose is 1mg once daily. Adjustment of dose should be made at intervals of 4 weeks or more. Doses should be individualized according to LDL-C levels, the goal of therapy and patient response. In children 6 to 9 years of age the maximum daily dose is 2mg. In children 10 years or older the maximum daily dose is 4mg. Children younger than 6 years of age: The safety and efficacy of Livazo in children below 6 years of age has not been established and no data are available.  Patients with impaired renal function No dosage adjustment is required in mild renal impairment but pitavastatin should be used with caution. Data with 4mg dose are limited in all grades of impaired renal function. Therefore 4mg dose should ONLY be used with close monitoring after graded dose titration. In those with severe renal impairment 4mg dose is not recommended Patients with mild to moderate impaired hepatic function The 4mg dose is not recommended in patients with mild to moderate impaired hepatic function. A maximum daily dose of 2mg may be given with close monitoring Method of Administration For oral use only and should be swallowed whole. Livazo can be taken at any time of the day with or without food. It is desirable that the patient takes the tablet at the same time each day. Statin therapy is generally more effective in the evening due to the circadian rhythm of lipid metabolism. If a child or adolescent is unable to swallow the tablet, where necessary, the tablet may be dispersed in a glass of water and taken immediately. To ensure accurate dosage a second volume of water should be used to rinse the glass and swallowed immediately. Tablets must not be dispersed in either acidic fruit juices or milk.

Препарат следует хранить в оригинальной упаковке в защищенном от света, недоступном для детей месте при температуре не выше 25°С.