Livazo

General characteristics. Structure:

Active agent - питавастатин calcium of 1.045 mg is equivalent to a pitavastatin of 1.0 mg
питавастатин calcium of 2.090 mg to an ekvivalentnopitavastatin of 2.0 mg
питавастатин calcium of 4.180 mg to an ekvivalentnopitavastatin of 4.0 mg

Excipients: лактозымоногидрат, the hydroxypropyl cellulose low-replaced a gipromelloza 6 Wednesday (Е 646), magnesium алюминометасиликат Type 1B, magnesium stearate, the water purified

Structure of a cover: Opadry White 03O28659, water purified

The composition of Opadry White dye 03o28659:gipromelloza 6 Wednesday (Е 646), titanium dioxide (Е 171), trietit citrate (Е 1505), silicon colloid anhydrous.

Pharmacological properties:

Pitavastatin competitively inhibits GMG-KOA-reduktazu, limiting the speed of effect of enzyme in biosynthesis of XC, and inhibits synthesis of XC in a liver. Thereof the expression of receptors of LPNP in a liver raises, promoting capture of the circulating LPNP in blood, to decrease in the general XC and XC LPNP of blood. Its resistant inhibition of hepatic synthesis of XC reduces secretion of LPNP in blood, reducing the TG level in a blood plasma.
Livazo reduces the increased LPNP level XC, the general XC and TG and increases the LPVP level XC. Drug reduces the level of apoliporotein (Apo-V) and leads to variable increase in Apo-A1 (table).
Table
Dose answer at patients with primary hypercholesterolemia (the adjusted average change percentage of initial level for 12 weeks).

Dose	N	HS-LPNSHCH	ZHS *	HS-LPVSHCH	TG	Apo-B	Apo-Al
Placebo	51	- 4,0	- 1,3	2,5	- 2,1	0,3	3,2
1 mg	52	- 33,3	- 22,8	9,4	- 14,8	- 24,1	8,5
2 mg	49	- 38,2	- 26,1	9,0	- 17,4	- 30,4	5,6
4 mg	50	- 46,5	- 32,5	8,3	- 21,2	- 36,1	4,7

Pharmacokinetics. Absorption: питавастатин it is quickly soaked up in upper parts of a GIT, and Cmax in a blood plasma is reached for 1 h after intake. Absorption does not depend on meal. Drug undergoes enterogepatichesky circulation in not changed look and is well soaked up in a small intestine. Absolute bioavailability of a pitavastatin makes 51%.
Distribution: питавастатин on> 99% contact proteins of a blood plasma, generally albumine and α1-кислотным a glycoprotein, and the average volume of distribution makes about 133 l. Pitavastatin is actively transported in hepatocytes, the scene of action and metabolism, many hepatic carriers, including OATP1B1 and OATP1B3. Plazmovy AUC changes with approximately 4-fold range between the highest and lowest values. Researches on SLCO1B1 (a gene which codes OATP1B1) give the chance to assume that polymorphism of this gene can explain big fluctuation of AUC. Pitavastatin is not substrate for a r-glycoprotein.
Metabolism: питавастатин in not changed look is the most part of drug in a blood plasma. The main metabolite — an inactive lactone which forms through a conjugate of a glucuronide of a pitavastatin of the radio UDP type of glyukuronoziltransferazy (UGT1A3 and 2B7). The researches in vitro with use of 13 isoforms of human P450 (CYP) cytochrome show that metabolism of a pitavastatin by means of CYP is minimum; CYP 2C9 (and to a lesser extent CYP 2CS) is responsible for metabolism of a pitavastatin to insignificant metabolites.
Removal from an organism: питавастатин in not changed look quickly it is brought out of a liver in bile, but is exposed to enterogepatichesky recirculation that predetermines duration of its action. Less than 5% of a pitavastatin are removed with urine. T½ from a blood plasma fluctuates of 5,7 h (1 dose) to 8,9 h (an equilibrium state), and the average geometrical peroral clearance is obvious makes 43,4 l/h after a single dose.
Influence of food: Cmax of a pitavastatin in a blood plasma decreased by 43% at use with food with high contents of fats, but AUC remained not changed.

Special groups of patients
Patients of advanced age: AUC of a pitavastatin is 1,3 times higher at patients aged> 65 years. It did not influence safety and efficiency of use of Livazo for patients of advanced age.
Floor: AUC of a pitavastatin is increased by 1,6 times at women. It did not influence safety and efficiency of use of Livazo for women.
Race: no distinction between pharmacokinetic profiles of a pitavastatin at healthy volunteers of Mongoloid and Caucasian races was noted.
Children: there are no pharmacokinetic data on use in pediatric practice.
Renal failure: for patients with a renal failure of average degree and patients on a hemodialysis of AUC value increased in 1,8 and 1,7 times respectively.
Livazo should appoint with care to persons with a renal failure of average or heavy degree. Increase in a dose should be carried out only at careful monitoring of function of kidneys after gradual titration of a dose. Patients with a renal failure of heavy degree are not recommended to apply a dose of 4 mg.
Liver failure: at patients with easy (a class A on classification of Chayld-Pyyu) a liver failure of AUC was 1,6 times higher, than at healthy volunteers, and at persons with a liver failure of average degree (a class B on classification of Chayld-Pyyu) AUC was 3,9 times higher. Restriction of a dose is recommended to patients with a liver failure of easy and average degree. Livazo is contraindicated to persons with a heavy liver failure.

Indications to use:

For the decrease increased the general XC and XC LPNP; to adult patients with primary hypercholesterolemia, including a heterozygous family hypercholesterolemia and the combined (mixed) dislipidemiya when reaction to a diet and other non-drug therapy is insufficient.

Route of administration and doses:

The tablet should not be chewed. Livazo can be accepted at any time, irrespective of meal. It is desirable that the patient took a pill at the same time daily. Therapy by statines, as a rule, is more effective in the evening in connection with a day-night rhythm of lipidic metabolism. Patients have to be on a diet with reduced contents of XC prior to treatment. It is important that patients continued to keep to a diet during treatment.
Adults. The usual initial dose makes 1 mg of 1 times a day. It is necessary to carry out dose adjustment at an interval of 4 weeks or more. Doses should be selected individually, according to the LPNP level XC, the scheme of therapy and a condition of the patient. Most of patients need the dose making 2 mg. The maximum daily dose — 4 mg.
Patients of advanced age. There is no need for dose adjustment.
Patients with renal failures. The usual initial dose makes 1 mg of 1 times a day. It is necessary to carry out dose adjustment at an interval of ≥4 weeks. Doses need to be selected individually, according to the LPNP level XC, the scheme of therapy and a condition of the patient.
At a renal failure of easy degree, dose adjustment it is not required, however питавастатин it is necessary to apply with care.
The dose of 4 mg at easy and average degree of a renal failure should be applied only at careful monitoring of function of kidneys after gradual titration of a dose.
Patients with a heavy renal failure are not recommended to apply a dose of 4 mg.
Patients with abnormal liver functions of easy and average degree. The dose of 4 mg is not recommended to patients with abnormal liver functions of easy and average degree. The maximum daily dose of 2 mg can be applied at careful monitoring of function of a liver.

Features of use:

Influence on muscles
As well as in case of use of other inhibitors of GMG-KOA-reduktazy (statines), there is a probability of development of a mialgiya, myopathy and the rabdomioliza is more rare. Patients should recommend to report about any discomfort from muscles. It is necessary to determine creatine kinase levels at any patient who reports about pain, sensitivity or weakness in muscles, especially if they are followed by an indisposition or fever.
The creatine kinase should not be defined after vigorous exercises or in the presence of any other reason of increase in its level, it can bring confusion in interpretation of result. At the increased concentration of a creatine kinase (> 5 times) the confirmatory test need to be carried out for 5–7 days.

Prior to treatment
As well as in case of use of other statines, Livazo needs to appoint with care to patients with tendency to development of a rabdomioliz. It is necessary to determine creatine kinase level for establishment of initial level in such situations: renal failure; hypothyroidism; personal or family anamnesis of inherited muscular disorders; muscular toxicity during use of a fibrat or other statine in the anamnesis; diseases of a liver or an alcohol abuse in the anamnesis; patients of advanced age (> 70 years) with other certain risk factors of development of a rabdomioliz.
In such situations clinical monitoring is recommended, it is necessary to estimate a ratio of possible risk and the expected advantage of treatment.

During treatment
Patients are recommended to report about pain, weakness or spasms in muscles right after their emergence. It is necessary to determine levels of a creatine kinase and to stop treatment at their increase in> 5 times in comparison with the upper bound of norm. It is necessary to consider a question of the treatment termination if muscular symptoms are heavy even if creatine kinase levels no more than by 5 times exceed the upper bound of norm. If symptoms disappear and levels of a creatine kinase are normalized, then it is possible to consider a question of treatment resuming by Livazo's drug in a dose of 1 mg and at careful monitoring.

Influence on a liver
As well as at use of other statines, patients should appoint Livazo's drug with care with a liver disease in the anamnesis or that who regularly takes excessive amount of alcohol. Prior to treatment by Livazo's drug and periodically during treatment it is necessary to control indicators of function of a liver. Patients need to stop Livazo's treatment with permanent increase in plasma transaminases (ALAT and ASAT) that exceeds the upper bound of norm by 3 times.

Influence on kidneys
Livazo needs to appoint with care to patients with a renal failure of average or heavy degree. Increase in a dose can be carried out only at careful monitoring of function of kidneys after gradual titration of a dose. Patients with a renal failure of heavy degree are not recommended to apply a dose of 4 mg.

Intersticial diseases of lungs
It was reported about intersticial diseases of lungs during use of some statines, especially at long-term therapy. The expressed signs can include short wind, unproductive cough and deterioration in the general state of health (fatigue, loss of body weight and fever). In case of suspicion on development of an intersticial disease of lungs in the patient therapy by statines needs to be stopped.

Other effects
Temporary suspension of therapy of Livazo it is recommended for treatment by erythromycin, other makrolidny antibiotics or fuzidovy acid. Livazo should appoint with care to the patients accepting drugs which lead to development of a myopathy (for example fibrata or Niacinum).

Lactose. Tablets contain lactose. Patients with the most rare hereditary intolerance of a galactose, deficit of lactase of Lapp or malabsorption of glucose galactose should not accept this medicine.
Use during pregnancy and feeding by a breast. Livazo is contraindicated during pregnancy and feeding by a breast. Women of reproductive age have to apply the appropriate measures of contraception during treatment by drug. As XC and other products of biosynthesis of XC are important for fetation, the potential risk of inhibition of GMG-KOA-reduktazy exceeds advantage of treatment during pregnancy. Researches on animals testify to reproductive toxicity, but lack of teratogenic potential. If the patient plans to become pregnant, therapy needs to be stopped at least a month before conception. If pregnancy occurs during use of drug of Livazo, therapy needs to be stopped immediately.
Livazo is contraindicated during feeding by a breast. Pitavastatin is allocated in breast milk at animals. It is unknown whether drug in breast milk at the person is emitted. In need of use of a pivastatin, it is necessary to refrain from breastfeeding.
Children. Drug is not used in pediatric practice.

Ability to influence speed of response at control of vehicles or work with mechanisms. Considering possibility of dizziness and drowsiness during treatment by Livazo's drug, it is necessary to refrain from control of vehicles and work with mechanisms.

Side effects:

The side reactions and their frequency observed at Livazo's use in the recommended doses during controlled clinical trials and during the post-marketing period are provided below according to classes of systems of bodies. Frequency is defined thus:
very often (≥1/10); often (≥1/100, <1/10); sometimes (≥1/1000, <1/100); isolated cases (1/10 000, <1/1000); the most rare (<1/10 000) and frequency is unknown.
Disturbance from system of blood and lymphatic system: sometimes — anemia.
Disbolism, metabolism: sometimes — anorexia.
Mental disorders: sometimes — sleeplessness.
Neurologic frustration: often — a headache; sometimes — dizziness, a dysgeusia, drowsiness.
Disturbance from an organ of sight: single — decrease in visual acuity.
Disturbance from an acoustic organ and a vestibular mechanism: sometimes — a ring in ears.
Gastrointestinal frustration: often — a lock, diarrhea, dyspepsia, nausea; sometimes — an abdominal pain, dryness in a mouth, vomiting; single — a glossodynia, acute pancreatitis.
Frustration of gepatobiliarny system: sometimes — increase in activity of transaminases (ASAT, ALAT); single — cholestatic jaundice, an aberration of indicators of function of a liver, a liver disease.
Changes from skin and hypodermic cellulose: sometimes — an itch, rash; single — a small tortoiseshell, an erythema.
Disturbance from a musculoskeletal system, connecting fabric and bones: often — a mialgiya, an arthralgia; sometimes — muscular spasms; single — a myopathy, рабдомиолиз.
Frustration from an urinary system: sometimes — a pollakiuria.
General frustration: sometimes — an adynamy, an indisposition, fatigue, peripheral hypostasis.
Increase in level of a kreatininkinaza in blood in> 3 times above the upper bound of norm was noted at 49 of 2800 (1,8%) the patients using Livazo's drug during controlled clinical trials. The levels by 10 times exceeding the upper bounds of norm and which are followed by symptoms from muscles (a mialgiya, a myopathy less often — рабдомиолиз), were single.
Post-marketing experience
The vast majority of patients in a research received 1 or 2 mg of a pitavastatin, but not on 4 mg. At 10,4% of patients the undesirable phenomena were noted, 7,4% of patients refused therapy in connection with the undesirable phenomena. The indicator of a mialgiya made 1,08%. The majority of the undesirable phenomena were lungs. The indicator of the undesirable phenomena was higher for 2 years at patients with a medicinal allergy (20,4%) or a disease of a liver, kidneys (13,5%) in the anamnesis.
During post-marketing observation there were 2 messages on a rabdomioliza, such patients needed hospitalization (0,01%).
Besides, are available spontaneous post-marketing the message on effects from skeletal muscles, including a mialgiya and a myopathy, for the patients applying Livazo in all recommended doses. Messages on development of a rabdomioliz with/without OPN, including a lethal rabdomioliz were also received.

Interaction with other medicines:

Pitavastatin is actively transported in hepatocytes in several ways (including polypeptide which transports organic anions, OATP) which can be involved in some of the following interactions.

Cyclosporine: simultaneous use of one dose of cyclosporine with Livazo brought in an equilibrium state to 4-, to 6-fold increase in AUC of a pitavastatin. Livazo is contraindicated to the patients applying cyclosporine.

Erythromycin: simultaneous use with Livazo's drug brought to 2-, to 8-fold increase in AUC of a pitavastatin. Temporary suspension of treatment of Livazo it is recommended for treatment by erythromycin or other makrolidny antibiotics.

Gemfibrozil and other fibrata: use of monotherapy of a fibratama sometimes is associated with development of a myopathy. Simultaneous use of fibrat with statines is associated with the increased risk of a myopathy and rabdomiolizy. Livazo should appoint with care along with fibrata. During the pharmacokinetic researches simultaneous use of drug of Livazo with gemfibrozily brought to 1-, to 4-fold increase in AUC of a pitavastatin, and AUC of a fenofibrat increased by 1,2 times.

Niacinum: researches of interaction of drug of Livazo and Niacinum were not conducted. Monotherapy by Niacinum was associated with development of a myopathy and rabdomiolizy. Thus, Livazo should appoint with care along with Niacinum.

Fuzidovy acid: there were messages on serious problems from muscles, such as рабдомиолиз, owing to interaction between fuzidovy acid and statines. For the period of treatment fuzidovy acid recommends temporary suspension of treatment of Livazo.

Rifampicin: the combined use with Livazo's drug brought to 1-, to 3-fold increase in AUC of a pitavastatin owing to decrease in absorption by a liver.

Protease inhibitors: can lead simultaneous use with Livazo's drug to minor changes of AUC of a pitavastatin.

Эзетимиб and its metabolite the glucuronide inhibits absorption of XC of food stuffs and bile. Simultaneous use with Livazo's drug does not influence the level of concentration of an ezetimib or its metabolite of a glucuronide in a blood plasma, and эзетимиб does not influence concentration of a pitavastatin in a blood plasma.

CYP 3A4 inhibitors: interaction researches with itrakonazoly and grapefruit juice, the known CYP 3A4 inhibitors, did not render clinically significant effect on plasma concentration of a pitavastatin.
The digoxin known R-gp substrate, does not interact with Livazo. At simultaneous use no considerable change of concentration of a pitavastatin or digoxin was observed.

Warfarin: equilibrium pharmacokinetic and pharmakodinamichesky properties (INR and PT) of warfarin at healthy volunteers did not depend on simultaneous use of Livazo on 4 mg/days. However, as well as in case of use of other statines, at the patients receiving warfarin it is necessary to control a prothrombin time or the international normalized ratio at inclusion of drug of Livazo in the scheme of therapy.

Contraindications:

• the known hypersensitivity to a pitavastatin or any of excipients or other statines;
• a liver failure of heavy degree, a liver disease in an active stage or permanent increase in serumal transaminases of the obscure etiology (in> 3 times are higher than the upper bound of norm);
• value of clearance of creatinine in> 5 times exceeds the upper bound of norm;
• myopathy;
• simultaneous therapy by cyclosporine.

Overdose:

At overdose strengthening of symptoms of side reactions is possible. There is no special therapy in case of overdose. A symptomatic treatment, in case of need it is necessary to carry out a maintenance therapy. It is necessary to control function of a liver and level of a creatine kinase. The hemodialysis is inefficient. There is no antidote.

Storage conditions:

In the place protected from light at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

On 7 or 10 tablets in a planimetric yacheykovoyupakovka from a film of polyvinyldichloride/polyvinyl chloride and aluminum foil.

On 1 (on 7 tablets) or 3 (on 10 tablets) blister strip packagings together with the instruction on a medical use nagosudarstvenny and Russian languages in a cardboard pack.