Livazo® [Pitavastatin]

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Available since: 2019-09-19

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Clinical Pharmacology

Pitavastatin competitively inhibits HMG-CoA reductase, limiting the rate of enzyme action in cholesterol biosynthesis, inhibits cholesterol synthesis (CH) in the liver. As a result, the expression of LDL receptors in the liver increases, contributing to the capture of circulating LDL in the blood, reducing total LDL and LDL cholesterol (LDL) in the blood. Its persistent inhibition of hepatic synthesis of Xc reduces the secretion of LDL in the blood, reducing triglyceride levels in the blood plasma.
Livazo reduces elevated levels of Xc-LDL, total Xs and triglycerides, and increases the level of HDL cholesterol (Xc-HDL). The drug reduces the level of apolipoproteins (Apo-B) and leads to a variable increase in Apo-A1.
Pharmacokinetics
Suction
Pitavastatin is rapidly absorbed in the upper GI tract, Cmax in the blood plasma is reached for 1 hour after ingestion. Suction does not depend on food intake. The drug in unchanged form passes enterohepatic circulation and is well absorbed in the small intestine. The absolute bioavailability of pitavastatin is 51%.
Pitavastatin Cmax in plasma decreased by 43% with a high-fat meal, but the AUC remained unchanged.
Distribution
Pitavastatin is more than 99% bound to plasma proteins, mainly albumin and α1-acid glucoprotein, with an average Vd of about 133 liters. Pitavastatin is actively transported to hepatocytes, the site of action and metabolism, by many hepatic carriers, including OATP1B1 and OATP1B3. AUC in plasma varies with approximately 4-fold range between the highest and lowest values. Studies on SLCO1B1 (the gene that encodes OATP1B1) suggest that the polymorphism of this gene may explain the large fluctuation of AUC. Pitavastatin is not a substrate for P-glucoprotein.
Metabolism
Pitavastatin unchanged is most of the drug in plasma. The main metabolite is the inactive lactone, which is formed through the conjugate of glucuronide pitavastatin ester type UDP glucuronosyltransferase (UGT1A3 and 2B7). In vitro studies using 13 isoforms of human cytochrome P450 (CYP) indicate that the metabolism of pitavastatin by CYP is minimal; CYP2C9 (and to a lesser extent CYP2C8) is responsible for the metabolism of pitavastatin to minor metabolites.
Removal
Pitavastatin in unchanged form is rapidly excreted from the liver to bile, but undergoes enterohepatic recirculation, which predetermines the duration of its action. Less than 5% of pitavastatin is excreted in the urine. T1 / 2 of blood plasma ranges from 5.7 h (1 dose) to 8.9 h (equilibrium state), the geometric mean of oral clearance is 43.4 l / h after a single dose.

Indications

Primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (hyperlipidemia type II, according to Fredrickson classification) or mixed hypercholesterolemia (hyperlipidemia type IIb according to Fredrickson classification), hypertriglyceridemia (type IV hyperlipidemia and Fredrikson classification, and in action;), and 201; for example, exercise, weight loss) are insufficient.

Composition

Active ingredient: pitavastatin calcium, which corresponds to the content of pitavastatin 1 mg,
Excipients: lactose monohydrate, low substituted hyprolose, hypromellose, magnesium aluminometasilicate, magnesium stearate.
The composition of the film shell: Opadry white, including hypromellose, titanium dioxide, triethyl acetate, colloidal silicon dioxide.

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Dosage and Administration

A pill is preferred at the same time a day, preferably in the evening, in accordance with the circadian rhythm of lipid metabolism. Patients should follow a cholesterol-lowering diet prior to treatment and during the process.
The initial dose of the drug 1 mg / day once. If necessary, the dose of the drug is increased at intervals of at least 4 weeks to 2 mg / day. The dose should be selected individually in accordance with the concentrations of LDL cholesterol, the purpose of treatment and the patient's response to treatment. Most patients require a dose of 2 mg. The maximum daily dose is 1 mg.
Patients with mild and moderately impaired liver function: a maximum daily dose of 2 mg is recommended.
Patients with impaired renal function: in case of impaired renal function of mild degree of gestia (it is desirable to objectively evaluate this degree with a reflection of QA or glomerular filtration rate), Livazo should be used with caution. Data on the use of the maximum daily dose of the drug 4 mg for impaired renal function of any severity is limited, therefore, it is necessary to prescribe the maximum daily dose of 4 mg only with careful monitoring of the kidney function after gradually increasing the dose. It is not recommended for patients with severely impaired renal function to prescribe a maximum daily dose of 4 mg; It is recommended to consider limiting the maximum daily dose to 2 mg in severe renal failure.
Patients of advanced age: dose adjustment is not required.

Adverse reactions

Frequency is defined as: very often (≥1 / 10), often (≥1 / 100 to <1/10), infrequently (≥1 / 1000 to <1/100), rarely (≥1 / 10 000 to <1 / 1000), very rarely (<1/10 000) and unknown.
Often: headache, constipation, diarrhea, indigestion, nausea, myalgia, pain in the joints.
Infrequently: anemia, anorexia, insomnia, dizziness, dullness of taste, drowsiness, tinnitus, abdominal pain, dry mouth, vomiting, increased transaminase (AST, ALT), skin itch, rash, muscle cramps, pollakiuria, asthenia, malaise, weakness, peripheral edema.
Rarely: reduced visual acuity, burning mouth syndrome, acute pancreatitis, cholestatic jaundice, abnormal liver function, abnormal liver function, myopathy, rhabdomyolysis, urticaria, erythema.
The following side effects have been identified with the use of certain statins: sleep disturbances, including nightmares, memory loss, sexual dysfunction, depression, isolated cases of interstitial lung disease, especially with prolonged therapy.

Contraindications

Severe hepatic impairment (more than 9 points on the Child-Pugh scale) or class C according to the Child-Pugh classification, liver disease and the active phase, including a persistent increase in the activity of hepatic transaminases in the blood serum (more than 3 times compared to VGN); myopathy; simultaneous administration of cyclosporine; pregnancy, breastfeeding, lack of adequate methods of contraception in women of childbearing age; age under 18 years (efficacy and safety not established); Hypersensitivity to pitavastatin, auxiliary components of the drug and other HMG-CoA reductase inhibitors (statins).

Drug interactions

Cyclosporine: with simultaneous use of a single dose of cyclosporine with Livazo in an equilibrium state, an increase in AUC of pitavastatin was observed by 4.6 times. Livazo is contraindicated in patients receiving cyclosporine.
Erythromycin: simultaneous use with Livazo caused an increase in the AUC of pitavastatin by a factor of 2.8. It is recommended to suspend the use of Livazo during the treatment with erythromycin or other macrolide antibiotics.
Gemfibrozil and other fibrates: the use of fibrates is sometimes associated with the development of myopathy. The simultaneous use of fibrates with statins increases the risk of myopathy and rhabdomyolysis.According to pharmacokinetic studies, the simultaneous use of pitavastatin with gemfibrozil caused an increase in AUC of pitavastatin 1.4 times, with fenofibrate an increase in AUC 1.2 times. In this regard, Livazo should be taken with caution at the same time with fibrates.
Niacin: Niacin monotherapy was associated with the development of myopathy and rhabdomyolysis. It is necessary to appoint Livazo with caution simultaneously with niacin.
Fuzidovaya acid: there were reports of serious problems with the muscles, such as rhabdomyolysis, due to the interaction between fusidic acid and statins. It is recommended to suspend the use of Livazo at the time of treatment with fusidic acid.
Rifampicin: simultaneous use of Livazo resulted in a 1.3-fold increase in AUC of pitavastatin due to a decrease in liver absorption (AUC decreased by 20%).
Protease inhibitors: the simultaneous use of Livazo can lead to minor changes in pitavastatin AUC.
Atazanavir is an inhibitor of OATP1B1 and liver glucuronotransferase UGT1A3 and UGT2B7 (responsible for the metabolism of pitavastatin). Simultaneous administration of atazanavir and Livazo led to an increase in AUC of pitavastatin 1.3 times, but did not affect the concentration of atazanavir (an increase in AUC 1.1 times).
Ezetimibe and its metabolite glucuronide inhibit cholesterol absorption from food and bile. Simultaneous use with pitavastatin does not affect the level of concentration of ezetimibe or its metabolite glucuronide in the blood plasma, and ezetimibe does not affect the concentration of pitavastatin in the blood plasma.
CYP3A4 inhibitors: Studies of drug interactions with itraconazole and grapefruit juice, known inhibitors of CYP3A4, have not had a clinically significant effect on pitavastatin plasma concentrations.
Digoxin, a known P-gp substrate, does not interact with Livazo. With simultaneous use, no significant change in the concentration of pitavastatin or digoxin was observed.
Warfarin: in equilibrium, pharmacokinetic and pharmacodynamic properties (INR and prothrombin time) of warfarin in healthy volunteers did not depend on the simultaneous use of Livazo at a dose of 4 mg / day. However, as in the case of the use of other statins, in patients taking warfarin, it is necessary to control the prothrombin time or INR when the Livazo drug is included in the treatment regimen.

Special instructions

Effect on muscle
Along with other inhibitors of HMG-CoA reductase (statins), it causes the development of myalgia, myopathy, less often rhabdomyolysis. Patients should be warned that they should immediately see a doctor if they develop any symptoms in the muscles. When patients have muscle pain or muscle weakness, especially if they are accompanied by malaise or fever, a determination of the level of creatine kinase is required.
Creatine kinase should not be measured after exercise or if there are any other possible causes of an increase in creatine kinase, which can be confusing when interpreting the results. After revealing an increased concentration of creatine kinase (more than 5 times as compared with VGN), a control analysis is required for 5-7 days and, if necessary, to stop taking the drug.
Before treatment
Livazo is prescribed with caution to patients with predisposing risk factors for the development of rhabdomyolysis. In the following cases, measurement of creatine kinase is required to establish standard baseline data:
- renal failure;
- reduced thyroid function;
- personal or family history of hereditary muscular disorders;
- previous case of muscle toxicity from fibrates or other statins;
- a history of liver disease or alcohol abuse;
- Elderly patients (over 70 years) with other predisposing risk factors for rhabdomyolysis.
In the process of treatment
In the event of severe muscular symptoms, therapy should be discontinued, even if the creatine kinase level is less than 5 times as compared with VGN. If the symptoms stop and the creatine kinase level returns to normal, then you can resume taking Livazo at a dose of 1 mg / day and with careful monitoring.
Effect on liver
Livazo should be used with caution in patients with a history of liver disease or in patients who abuse alcohol. Before starting treatment with Livazo and periodically during the entire course of therapy, it is necessary to monitor indicators of liver function. Treatment should be discontinued in patients with a persistent increase in plasma transaminases (ALT and AST) more than 3 times as compared with VGN.
Impact on the kidneys
Livazo should be used with caution in patients with moderate to severe renal insufficiency. Increasing the dose should be done only with careful monitoring of renal function after gradual titration of the dose. Patients with severe renal insufficiency are not recommended to use a dose of 4 mg.
Interstitial lung disease
Interstitial lung diseases have been reported during the use of certain statins, especially with long-term therapy. Severe symptoms may include shortness of breath, an unproductive cough and worsening of general health (fatigue, loss of body weight and fever). In case of suspected development of interstitial lung disease in a patient, statin therapy should be stopped.
Influence on ability to drive motor transport and control mechanisms
There are no data on the impact on the ability to drive a vehicle and control moving mechanisms.

Overdosage

Overdose may increase the symptoms of adverse reactions.
There is no specific antidote. Symptomatic treatment and supportive measures should be carried out as needed.
Indicators of liver function and creatine kinase levels must be monitored. Hemodialysis is ineffective.