Ксарелто®

General characteristics. Structure:

Active agent: ривароксабан micronized - 10 mg
Excipients: cellulose microcrystallic - 40 mg, croscarmellose sodium - 3 mg, a gipromelloza 5 Wednesday - 3 mg, lactoses monohydrate - 27,90 mg, magnesium stearate of-0,60 mg, sodium a lauryl sulfate - 0,50 mg; cover: ferrous oxide red - 0,015 mg, a gikpromelloza 15 Wednesday of-1,500 mg, a macrogoal of 3350 - 0,500 mg, titanium dioxide - 0,485 mg.

Description
Round biconvex tablets of pink color film coated; the method of expression put an engraving: on one party - a triangle with designation of a dosage (10), on another - a branded bayerovsky cross. A type of a tablet in a break: the odnokrodny mass of white color surrounded with a cover of pink color.

Pharmacological properties:

Pharmacodynamics.

Action mechanism

Rivaroksaban - the high-selection direct inhibitor of a factor Ha having high bioavailability at intake.

Activation of a factor of X with formation of a factor Ha in internal and external ways of coagulation plays the central role in the coagulative cascade.

Pharmakodinamichesky effects

At the person the dozozavisimy inhibition of a factor Ha was observed. Rivaroksaban exerts dozozavisimy impact on a prothrombin time and close correlates with concentration in plasma (=0,98) if for the analysis the Neoplastin® set is used. When using other reactants results will differ. The prothrombin time should be measured in seconds as INR (the international normalized relation) is calibrated and certified only for derivatives of coumarin and it cannot be applied to other anticoagulants. At patients to whom big orthopedic operations are performed 5/95 percentiles for a prothrombin time (Neoplastin®) in 2-4 hours after reception of a tablet (i.e. on an effect maximum) vary from 13 to 25 seconds. Also ривароксабан дозозависимо increases the activated partial tromboplastinovy time (APTT) and result of HepTest®; however these parameters are not recommended to be used for assessment of pharmakodinamichesky effects of a rivaroksaban. Rivaroksaban also influences activity Anti-ha of a factor, however standards for calibration are absent.

During treatment rivaroksabany it is not required to carry out monitoring of parameters of a blood coagulation.

At healthy men and women 50 years are more senior lengthening of an interval of QT under the influence of a rivaroksaban was not observed.

Pharmacokinetics. Absorption and bioavailability

Absolute bioavailability of a rivaroksaban after reception of a dose of 10 mg high (80-100%). Rivaroksaban is quickly soaked up; maximum concentration (Smaks.) it is reached in 2-4 hours after reception of a tablet.

At reception of a rivaroksaban in a dose of 10 mg with food AUC change (the area under a curve "concentration - time") and Smaks is noted. (maximum concentration). Rivaroksaban in a dose of 10 mg can be appointed for inclusion in time of food or irrespective of meal.

The pharmacokinetics of a rivaroksaban is characterized by moderate individual variability; individual variability (variation coefficient) makes from 30% to 40%, except for day of carrying out surgical intervention and the next day when variability in exposure high (70%).

Distribution

In a human body the most part of a rivaroksaban (92-95%) contacts proteins of plasma, the main connecting component is a seralbumin. Distribution volume - moderate, makes Vss about 50 l.

Metabolism and removal

At intake about 2/3 from the appointed dose of a rivaroksaban is exposed to metabolism and further it is removed by equal parts with urine and a stake. The remained third of a dose is removed by means of direct renal excretion in not changed look, mainly, due to active renal secretion.

Rivaroksaban is metabolized by means of isoenzymes of CYP3A4, CYP2J2, and also by means of the mechanisms independent of system of tsitokhrom. The main sites of biotransformation are oxidation of morpholine group and hydrolysis of amide bonds.

It agrees to the data obtained by in vitro ривароксабан is substrate for proteins carriers R-gp (R-glycoprotein) and Bcrp (protein of resistance to a breast cancer).

Not changed ривароксабан is the only active connection in human plasma, the significant or active circulating metabolites in plasma are not found. Rivaroksaban whose system clearance makes about 10 l/h can be carried to medicinal substances with the low level of clearance. At removal of a rivaroksaban from plasma the final elimination half-life makes from 5 to 9 hours at young patients and from 11 to 13 hours - at elderly patients.

Floor / Advanced age (65 years are more senior)

At elderly patients of concentration of a rivaroksaban in plasma is higher, than at young patients, average AUC value approximately by 1,5 times exceeds the corresponding values at young patients, mainly, owing to the seeming decrease in the general and renal clearance.

Clinically significant distinctions of pharmacokinetics are not found in men and women. Body weight

Too small or big body weight (less than 50 kg and more than 120 kg) only slightly influences concentration of a rivaroksaban in plasma (distinction makes less than 25%).

Children's age

Data on this age category are absent. Interethnic distinctions

Clinically significant distinctions of pharmacokinetics and pharmacodynamics at patients of a Caucasian, Afro-American, Latin American, Japanese or Chinese ethnic origin were not observed.

Liver failure

Influence of a liver failure on pharmacokinetics of a rivaroksaban was studied at the patients distributed on classes according to classification of Chayld-Pyyu (according to standard procedures in clinical trials). Classification of Chayld-Pyyu allows to estimate the forecast of chronic diseases of a liver, mainly, of cirrhosis. At patients to whom performing anticoagulating therapy is planned especially important critical point of an abnormal liver function is reduction of synthesis of blood-coagulation factors in a liver. As this indicator corresponds only to one of five clinical/biochemical criteria making classification of Chayld-Pyyu, the risk of development of bleeding not absolutely accurately correlates with this classification. The issue of treatment of similar patients has to be resolved by anticoagulants irrespective of a class on classification of Chayld-Pyyu.

Rivaroksaban is contraindicated to patients with the liver diseases proceeding with the coagulopathy causing clinically significant risk of bleedings. At patients with cirrhosis with easy degree of a liver failure (a class A on Chayld-Pyyu) the pharmacokinetics of a rivaroksaban only slightly differed (increase in AUC of a rivaroksaban in 1, 2 times was on average noted) from the corresponding indicators in control group of healthy examinees. Significant distinctions of pharmakodinamichesky properties between groups were absent.

Patients with cirrhosis and liver failure of moderate severity (a class B on Chayld-Pyyu) had significantly raised average AUC of a rivaroksaban (by 2,3 times) in comparison with healthy volunteers owing to significantly reduced clearance of the medicinal substance indicating a serious disease of a liver. Suppression of activity of a factor Ha was expressed stronger (by 2,6 times), than at healthy volunteers. The prothrombin time also by 2,1 times exceeded indicators at healthy volunteers. By means of measurement of a prothrombin time the external way of coagulation including factors of coagulation of VII, X, V, II and I which are synthesized in a liver is estimated. Patients with a medium-weight liver failure are more sensitive to a rivaroksaban that is a consequence of closer interrelation of pharmakodinamichesky effects and pharmacokinetic parameters, especially between concentration and a prothrombin time.

Data on patients with a liver failure of a class C on classification of Chayld-Pyyu are absent.

Renal failure

At patients with a renal failure increase in concentration of a rivaroksaban in a blood plasma, inversely proportional to decrease in renal function, estimated on clearance of creatinine was observed.

At patients with a renal failure easy (clearance of creatinine of 80-50 ml/min.), average degree (clearance of creatinine <50-30 ml/min.) or heavy (clearance of creatinine <30-15 ml/min.) also 1,6-fold increase in concentration of a rivaroksaban in plasma (AUC) respectively in comparison with healthy volunteers was observed 1,4-, 1,5-. The corresponding increase in pharmakodinamichesky effects was more expressed. At patients with a slight, medium-weight and heavy renal failure the general suppression of activity of a factor Ha increased in 1,5, 1,9 and 2 times in comparison with healthy volunteers; a prothrombin time owing to action of a factor Ha also in 1,3, 2,2 and 2,4 times - respectively.

Data on use of a rivaroksaban for patients with clearance of creatinine of 30-15 ml/min. are limited in this connection it is necessary to be careful at use of drug for this category of patients. Data on use of a rivaroksaban for patients with clearance of creatinine <15 ml/min. are absent in this connection it is not recommended to use drug for this category of patients.

Indications to use:

Prevention of a venous thromboembolism (VTE) at the patients who are exposed to big orthopedic operative measures on the lower extremities.

Route of administration and doses:

Inside, irrespective of meal.
For prevention of VTE at big orthopedic operations about 1 tablet is recommended to appoint 10 mg of 1 times a day. Treatment duration:
- 5 weeks after big operation on a hip joint;
- 2 weeks after big operation on a knee joint.
The initial dose should be accepted in 6-10 hours after operation on condition of the reached hemostasis.
In case of the admission of a dose the patient should accept ривароксабан immediately and next day to continue treatment on 1 tablet a day, as well as earlier.

Separate groups of patients
Dose adjustment depending on age of the patient (65 years are more senior), a floor, body weight or ethnic group is not required.

Patients with a liver failure
Rivaroksaban is contraindicated to patients with the liver diseases which are followed by a coagulopathy which causes clinically significant risk of bleeding. With other diseases of a liver of change of a dose it are not required for patients. The available limited clinical data obtained at patients with a medium-weight liver failure (a class B on Chayld-Pyyu), indicate significant strengthening of pharmacological activity of drug. For patients with a heavy liver failure (a class C on Chayld-Pyyu) clinical data are absent.

Patients with a renal failure
At purpose of a rivaroksaban the patient with easy (clearance of creatinine of 80-50 ml/min.) or medium-weight (the clearance of creatinine <50-30 ml/min.) a dose decline is not required by a renal failure.
The available limited clinical data obtained at patients with a heavy renal failure (clearance of creatinine <30-15 ml/min.), show significant increase in concentration of a rivaroksaban at these patients. ривароксабан it is necessary to apply to treatment of this category of paktsiyent with care.
Use of a rivaroksaban is not recommended at patients with clearance of creatinine <15 ml/min.

Transfer of patients from the antagonists of vitamin K (AVK) on Ksarelto® At transfer of the patient with AVK on Ksarelto®, value of an indicator of MNO will increase in a false manner after reception of Ksarelto®. In this regard the indicator of MNO cannot be used for control of anticoagulating effect of Ksarelto®.

Transfer of patients with Ksarelto® on the antagonists of vitamin K (AVK) Exists probability of insufficient anticoagulating effect at transfer of patsikent with Ksarelto® on AVK. During the transition period connected with transfer into other anticoagulative drug it is necessary to provide continuous and sufficient anticoagulating effect. It must be kept in mind that Ksarelto® can promote increase in an indicator of MNO.
At transfer of the patient with Ksarelto® on AVK, both drugs it is necessary to give at the same time until MNO does not reach value> 2,0. In the first two days of a transition period it is necessary to use a standard dose of AVK, and afterwards to be guided by MNO value. During joint reception of Ksarelto® and ABK MHO it is necessary to define not earlier than in 24 hours (after previous, but before reception of the following dose of Ksarelto®). After cancellation of Ksarelto® definition of MNO with sufficient degree of reliability is possible in 24 hours after reception of the last dose of drug (see. "Interaction with other medicines and other forms of interaction").

Transfer of patients on Ksarelto® At transfer of the patient from parenteral anticoagulants on Ksarelto®, reception of Ksarelto® should be begun with parenteral anticoagulants in 0-2 hours prior to alleged introduction of the following dose of parenteral drug (e.g. NMG) or during cancellation it is long the used parenteral drug (e.g. intravenous unfractionated heparin).

Transfer of patients with Ksarelto® on parenteral anticoagulants
To stop reception of Ksarelto® and to enter the first dose of parenteral anticoagulant in
time of alleged reception of the following dose of Ksarelto®.

Features of use:

Antitrombotichesky drugs, including ривароксабан, should be iskpolzovat with care in treatment of patients with the increased risk of bleeding (see the section "With Care").
At patients with a heavy renal failure (clearance of creatinine <30 ml/min.) concentration of a rivaroksaban in plasma can be significantly increased that can result in the increased risk of bleedings. Owing to a basic disease for these patients the risk both bleeding, and thrombosis is increased (see the section "With Care").
Use of a rivaroksaban was not studied in clinical trials at the operative measures undertaken at hip fractures (see the section "Contraindications").
At inexplicable decrease in hemoglobin or arterial pressure it is necessary to look for a bleeding point.
Against the background of treatment rivaroksabany lengthening of an interval of QT was not observed.
When performing a spinal puncture and epidural/spinal anesthesia for the patients receiving inhibitors of aggregation of thrombocytes for the purpose of prevention of tromboembolic episodes there is a risk of development of an epidural or spinal hematoma which can lead to long paralysis. The risk of these events increases further when using constant catheters or the accompanying use of the medicines influencing a hemostasis. An injury when performing an epidural or spinal puncture or a repeated puncture can also promote increase in risk. Patients have to be under observation for identification of signs or symptoms of neurologic disturbances (for example, numbness or weaknesses of legs, dysfunctions of intestines or a bladder). At detection of neurologic frustration urgent diagnosis and treatment is necessary. The doctor has to compare potential advantage and risk before carrying out spinal intervention to the patients receiving anticoagulants or preparing for receiving anticoagulants for the purpose of prevention of thrombosis. The epidural catheter is taken not earlier than in 18 hours after purpose of the last dose of a rivaroksaban. Rivaroksaban it is not necessary to appoint earlier, than in 6 hours after extraction of an epidural catheter. In case of a traumatic puncture purpose of a rivaroksaban should be postponed for 24 hours.
The data on safety received from preclinical trials
Except for the effects connected with strengthening of pharmacological action (bleedings) in the analysis of the preclinical data obtained in researches on pharmakoklogichesky safety, specific danger to the person is not revealed.

Side effects:

Safety of a rivaroksaban of 10 mg was estimated in four researches of the 3rd phase with participation of 6097 patients which performed large orthopedic lower extremity operation (total prosthetics of a knee or hip joint), receiving treatment lasting up to 39 days.

Adverse reactions are classified by the frequency of occurrence and systems of bodies, and they should be interpreted taking into account a surgical situation.

Considering the action mechanism, use of a rivaroksaban can be followed by the increased risk of the concealed or explicit hemorrhage from any bodies and fabrics which can lead to posthemorrhagic anemia. Signs, symptoms and severity (including a possible lethal outcome) vary depending on localization, severity or duration of bleeding and/or anemia. The risk of development of bleedings can increase at patients with uncontrollable arterial hypertension and/or at combined use with the drugs influencing a hemostasis. Hemorrhagic complications can be shown by weakness, pallor, dizziness, a headache, short wind, and also increase in an extremity in volume or shock, inexplicable other reasons. In certain cases owing to anemia myocardium ischemia symptoms, such as a stethalgia and stenocardia can develop. Therefore at assessment of a condition of the patient receiving anticoagulants it is necessary to consider the possibility of hemorrhage.

The generalized data on the frequency of the undesirable reactions registered for Ksarelto® are given in the table below. In frequency groups undesirable effects are presented as reduction of their weight. Depending on the frequency of emergence were allocated frequent (> 1/100 and <1/10), infrequent (> 1/1000 and <1/100) and rare undesirable reactions (> 1/10000 and <1/1000). Undesirable reactions which were revealed only at a stage of post-market observation researches or for which it was impossible to make frequency assessment are designated as "frequency is unknown".

Table 1: All undesirable reactions which arose during treatment at the patients participating in clinical trials of the III phase

Systems of bodies	Often > 1% and <10%	Infrequently > 0,1% and <1%	Seldom > 0,01% and <0,1%
Disturbances from circulatory and lymphatic system		Anemia (including the corresponding laboratory parameters) Trombotsitemiya (including the increased maintenance of thrombocytes)
Disturbances from heart		Tachycardia
Disturbances from the alimentary system	Nausea	Lock Diarrhea Abdominal pain (including pain in an upper part of a stomach, a sensation of discomfort in a stomach) Dyspepsia (including discomfort in epigastriums) Dryness in a mouth Vomiting
Disturbances from a liver			Abnormal liver functions
System disturbances and states in a drug injection site	Fever Peripheral hypostases	Local hypostasis Deterioration in overall health (including weakness, an adynamy)	Feeling sick (including a sensation of discomfort)
Disturbances from immune system			Allergic dermatitis
Injuries, poisonings and procedural complications	Hemorrhages after the carried-out procedures (including postoperative anemia and bleeding from a wound)	Allocations from a wound
Results of researches	Increase in the GGT level Increase in level of transaminases (including ALT, nuclear heating plant)	Increase in activity of a lipase Increase in activity of amylase Increase in concentration of bilirubin Increase in activity of LDG Increase in activity of an alkaline phosphatase	Increase in concentration of the conjugated bilirubin (at the accompanying increase in activity of ALT or without it)
Disturbances from a musculoskeletal system and connecting fabric		Extremity pain
Disturbances from a nervous system		Dizziness Headache	Short-term loss of consciousness (including syncopal states)
Disturbances from kidneys and urinary ways		Renal failure (including increase in concentration of creatinine, increase in concentration of urea)
Disturbances from skin and hypodermic fabrics		Pour an itch (including exceptional cases of a generalized itch) Posttraumatic hematomas	Small tortoiseshell (including exceptional cases of a generalized small tortoiseshell)
Disturbances from vessels		Hypotension (including a lowering of arterial pressure, hypotension when holding procedures) the Hematoma (including exceptional cases of hemorrhages in muscles) Bleedings from digestive tract (including odontorrhagias, a rectum, a hematemesis) Hemorrhage from urinogenital ways Nasal bleedings

• In other clinical trials of a rivaroksaban separate cases of hemorrhage in adrenal glands and a conjunctiva, and also a digestive tract helcomenia with a lethal outcome are described; jaundice and hypersensitivity was in rare instances noted; infrequently - a pneumorrhagia. Single intracranial bleedings (especially at patients with an arterial hypertension and/or accepting the accompanying medicines influencing a hemostasis (for example, NPVS, antiagregant or other antitrombotichesky means)) which in some cases can be potentially life-threatening are described.

According to other clinical trials it was reported about emergence of a vascular pseudoaneurysm after transdermal interventions.

According to other clinical trials and post-market observation researches it was reported about the known complications of bleedings, such as a kompartment-syndrome. Besides, development of an acute renal failure and renal failure which were a consequence of bleeding which intensity was sufficient was registered to cause hypoperfusion.

Features of effect of medicine at the first reception and at its cancellation:
It is inapplicable

Interaction with other medicines:

Pharmakokineti chesky interactions
Removal of a rivaroksaban is carried out mainly by means of the metabolism in a liver mediated by system of P450 cytochrome (CYP3A4, CYP2J2) and also - by renal excretion of not changed medicinal substance with use of systems of carriers of P-gp/Bcrp (Р-гликопротеина / a squirrel of stability of a breast cancer) (see the section "Pharmacokinetics").
Rivaroksaban does not suppress and does not induce an isoenzyme of CYP3A4 and other important iso-forms of cytochrome.
Simultaneous use of a rivaroksaban and strong inhibitors of an isoenzyme CYP3A4 and R-glycoprotein can lead to decrease in renal and hepatic clearance and, thus, is significant increase system influence.
Combined use of a rivaroksaban and azolovy antifungal means of the ketoko-nazol (400 mg of 1 times a day) which is strong CYP3A4 inhibitor and the R-glycoprotein led to increase in a rivaroksaban by average equilibrium AUC by 2,6 times and to increase in average Smaks. a rivaroksabana by 1,7 times that was followed by significant strengthening of pharmakodinamichesky effects of drug.
Joint purpose of a rivaroksaban and inhibitor of HIV protease of the ritonavir (600 mg 2 times a day) which is strong CYP3A4 inhibitor and the R-glycoprotein led to increase in a rivaroksaban by average equilibrium AUC by 2,5 times and to increase in average Smaks. a rivaroksabana by 1,6 times that was followed by significant strengthening of pharmakodina-michesky effects of drug.
In this regard ривароксабан it is not recommended to use for the patients receiving system treatment by antifungal drugs of azolovy group or inhibitors of HIV protease (see the section "With Care").
It is expected that other medicinal substances which are strongly oppressing only one of ways of removal of a rivaroksaban - with participation of CYP3A4 or R-glycoprotein, will increase concentration of a rivaroksaban in plasma to less significant values.
Klaritromitsin (500 mg 2 times a day), strongly overwhelming isoenzyme of CYP3A4 and umekrenno an overwhelming R-glycoprotein, caused increase in AUC values by 1.5 times and Smaks. a rivaroksabana by 1,4 times. This increase has an order of normal variability of AUC and Smaks. also it is considered clinically insignificant.
Erythromycin (500 mg 3 times a day), moderately overwhelming isoenzyme of CYP3A4 and the R-glycoprotein, caused increase in AUC values and Smaks. a rivaroksabana by 1,3 times. This increase has an order of normal variability of AUC and Smaks. also it is considered clinically insignificant.
Flukonazol (400 mg of 1 times a day), moderately overwhelming isoenzyme of CYP3A4, caused increase in AUC values by 1,4 times and Smaks. a rivaroksabana by 1,3 times. This increase has an order of normal variability of AUC and Smaks. also it is considered clinically insignificant.
Joint purpose of the rivaroksaban and rifampicin which is a strong induktokr of CYP3A4 and the R-glycoprotein led to decrease in a rivaroksaban by average AUC approximately by 50% and parallel reduction of its pharmakodinamichesky effects. Combined use of a rivaroksaban with other strong inductors CYP3A4 (for example, Phenytoinum, carbamazepine, phenobarbital or drugs of the St. John's Wort which is made a hole) can also lead to decrease in concentration of a rivaroksaban in plasma. Reduction of concentration of a rivaroksaban in plasma is recognized as clinically insignificant.
Pharmakodinamichesky interactions
After the combined purpose of an enoksaparin of sodium (a single dose of 40 mg) and a ri-varoksaban (a single dose of 10 mg) the summatsionny effect concerning activity of an anti-factor Ha which was not followed by additional summatsionny effects concerning tests on coagulability of blood (a prothrombin time, AChTV) was observed. Enoksaparin did not change pharmacokinetics of a rivaroksaban.
After joint purpose of a rivaroksaban in a dose of 15 mg and Naproxenum in a dose of 500 mg of clinically significant lengthening of a bleeding time it was not observed. Nevertheless, at individuals more expressed pharmakodinamichesky answer is possible. Pharmacokinetic interaction between rivaroksabany in a dose of 15 mg and klopidogrely is not revealed (a shock dose of 300 mg with the subsequent purpose of maintenance doses of 75 mg), but at a part of patients the significant increase in a bleeding time which was not correlating with aggregation of thrombocytes and content of R-selectin or a GPIIb/IIIa-receptor is revealed.
Transfer of patients from warfarin (MNO from 2,0 to 3,0) on ривароксабан (20 mg) or from a rivakroksaban (20 mg) on warfarin (MNO from 2,0 to 3,0) was followed by the more than additive increase in a prothrombin time / (MNO (Neoplastin) (in some cases to 12) whereas effects of change of aChTV, suppression of activity of a factor of Xa and the endogenous potential of thrombin (EPT) were the additive.
For assessment of pharmakodinamichesky effects of Ksarelto® during a transition period it is possible prokvest the analysis Anti-ha for factor activity, PiCT and HepTest if the indicators defined in their course were not affected by warfarin.
Since 4th day after warfarin cancellation, all analyses (including PV, aChTV, suppression of activity of a factor of Xa and EPT) reflected only effect of Ksarelto® (see the section "Sposobprimeneniya and Doses").
For assessment of pharmakodinamichesky effects of warfarin during a transition period it is possible to iskpolzovat MNO indicator measured at the time of achievement Smin of a rivaroksaban (in 24 hours after reception of a dose of a rivaroksaban) as in this timepoint influence of a riva-roksaban on results of the analysis is minimum.
Pharmacokinetic interaction between warfarin and Ksarelto® is not revealed. The accompanying use of other drugs
Clinical significant pharmacokinetic or pharmakodinamichesky interactions at simultaneous use of a rivaroksaban with midazolam (substrakty CYP3A4), digoxin (R-glycoprotein substrate) or atorvastatiny were not noted (CYP3A4 and P-gp substrate).
Clinically significant interaction with food was not noted.

Incompatibility
It is unknown

Influence on laboratory parameters
Influence on results of tests on coagulation parameters (prothrombin time, AChTV, HepTest®) corresponds to Ksarelto® expected taking into account the mechanism of action.

Contraindications:

- Hypersensitivity to the rivaroksaban or any excipients which are contained in a tablet.
- Clinically significant active bleedings (for example, intracranial bleedings, gastrointestinal bleedings).
- The liver diseases proceeding with a coagulopathy which causes clinically significant risk of bleeding.
- Pregnancy and period of a lactation (breastfeeding period).
- Children's and teenage age up to 18 years (efficiency and safety for patients of this age group are not established).
- Use of a rivaroksaban was not studied in clinical trials at operative measures at patients concerning a femur fracture. Therefore use of a rivaroksaban is not recommended for this category of patients.
- Clinical data on use of a rivaroksaban for patients with a heavy renal failure (clearance of creatinine <15 ml/min.) are absent. Therefore use of a rivaroksaban is not recommended for this category of patients.
- A hereditary lactose intolerance or galactoses (for example, the caused insufficiency of lactase or malabsorption of glucose galactose) as lactose is a part of this medicine.

WITH CARE:

With care it is necessary to use drug:

• At treatment of patients with the increased risk of bleeding (including at the inborn or acquired tendency to bleedings, an uncontrollable heavy arterial hypertension, a peptic ulcer of a stomach and a 12-perstny gut in a stage of an aggravation, recently postponed peptic ulcer of a stomach and a 12-perstny gut, a vascular retinopathy, recently postponed intracraneal or intracerebral bleeding, at pathology of vessels back or a brain, after recently undergone a head, spinal cord or eyes operation).

• At treatment of patients with a renal failure of moderate severity (clearance of creatinine of 49-30 ml/min.) receiving at the same time the drugs increasing the level of a rivaroksaban in a blood plasma.

• At treatment of patients (clearance of creatinine between 29-15 ml/min.) it is necessary to be careful with a heavy renal failure as owing to a basic disease such patients are subject to the increased risk of both bleeding, and a thrombogenesis.

• Rivaroksaban is not recommended to use for the patients receiving system treatment by antifungal drugs of azolovy group (for example, ketokonazoly) or HIV protease inhibitors (for example, ritonaviry). These medicines are strong inhibitors of an isoenzyme CYP3A4 and P-glycoprotein. As a result, these medicines can increase concentration of a rivaroksaban in plasma to clinically significant level that increases risk of development of bleedings (see the section "Interaction with Other Medicines").

Patients with a heavy renal failure or the increased risk of bleeding and the patients receiving the accompanying system treatment by antifungal drugs of azolovy group or inhibitors of HIV protease after an initiation of treatment have to be under fixed control for timely detection of complications in the form of bleedings. Such control can include regular physical inspection of patients, careful observation for separated on a drainage of a surgical wound and consecutive measurements of level of hemoglobin. Any depreciation in hemoglobin or arterial pressure for which there is no explanation is the basis for search of the place of bleeding.

• At the patients receiving the medicines influencing a hemostasis (for example, NPVS, antiagregant or other antitrombotichesky means).

• Patients with risk have aggravations of a peptic ulcer of a stomach and a 12-perstny gut purpose of preventive antiulcerous treatment can be justified.

Use at pregnancy and a lactation

Pregnancy
Data on use of a rivaroksaban for pregnant women are absent.
The data obtained on experimental animals showed the expressed toxicity of a rivaroksaban for a maternal organism connected with pharmacological effect of drug (for example, complications in the form of hemorrhages) and resulting in reproductive toxicity.
Owing to possible risk of development of bleeding and ability to get through a placenta ривароксабан it is contraindicated at pregnancy.
Women with the kept reproductive ability should use effective methods of contraception during treatment rivaroksabany.
Lactation
Data on use of a rivaroksaban for treatment of women in the period of a lactation are absent. The data obtained on experimental animals show what ривароксабан is allocated with breast milk. Rivaroksaban can be applied only after breastfeeding cancellation.

Fertility
In doses to 200 mg/kg ривароксабан does not exert impact on male or female fertility.

Influence on ability to manage motor transport / to work with moving mechanisms.

Researches of influence of a rivaroksaban on ability to control of motor transport and work with potentially dangerous moving mechanisms were not conducted.
In the postoperative period cases of faints and dizziness were infrequently noted (see the section "Side effect"). Patients who have these adverse reactions should not manage motor transport or to work with moving mechanisms.

Overdose:

It was reported about exceptional cases of overdose to 600 mg without complications in a look a krovotechekniya or other undesirable reactions. Owing to limited absorption the effect of saturation without further increase in average content of a rivaroksaban in plasma at hyper therapeutic doses in 50 mg is expected or above. The specific antidote of a rivaroksaban is unknown.
In case of overdose for decrease in absorption of a rivaroksaban it is possible to use absorbent carbon.
Considering intensive linkng with proteins of plasma, it is expected that ривароксабан it will not be removed when carrying out dialysis.
At emergence of a complication in the form of bleeding, the following reception has to be postponed or treatment has to be cancelled, depending on a situation. The elimination half-life of a rivaroksaban makes about 5-13 hours (see the section "Pharmakokineti"). Treatment should be selected individually, according to weight and localization of bleeding.
If necessary the corresponding symptomatic treatment, for example, a mechanical compression (for example, in case of severe nasal bleeding), a surgical hemostasis with procedures of control of bleeding, completion of volume of liquid and hemodynamic support, blood preparations (a packed red cells or freshly frozen plasma, depending on the accompanying anemia or a coagulopathy) or thrombocytes can be applied.
If the listed above actions do not lead to elimination of bleeding, the specific pro-coagulant, for example a concentrate of a prothrombin complex, a concentrate of the activated prothrombin complex or a recombinant factor of Vila (if Vila) can be appointed.

However so far experience of use of these drugs at treatment of the patients receiving ривароксабан is very limited.
It is expected that protamin sulfate and vitamin K will not exert impact on anticoagulative activity of a rivaroksaban.
Experience of use of anti-fibrinolitic means (traneksamovy acid, aminocapronic acid) at the persons receiving Ksarelto® no. Scientific justification of expediency or experience of use of system haemo static desmopressin or Aprotininum at the persons receiving Ksarelto® no.

Storage conditions:

Period of validity 3 years. Not to use after the period of validity specified on packaging. At a temperature not above 30 °C to Store in the place, unavailable to children! Precautionary measures at destruction of unused medicines: It is inapplicable.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 10 mg.
On 5 or on 10 tablets in blisters from software Is scarlet / or Is scarlet / ПВХ-ПВДХ.
1 blister with 5 tablets, 1, 3 or 10 blisters with 10 tablets in a cardboard pack together with the application instruction.