ARIKSTRA
Active material: fondaparinux sodium
When ATH: B01AX05
CCF: The anticoagulant of direct action – selective inhibitor of factor Xa
ICD-10 codes (testimony): I20.0, I21, i26, I74, I82
When CSF: 01.12.11.06.02
Manufacturer: GlaxoSmithKline (France)
Pharmaceutical form, composition and packaging
The solution for the p / to the introduction clear, colorless, without visible mechanical inclusions.
| 1 syringe | |
| fondaparinux sodium | 2.5 mg |
Excipients: sodium chloride, hydrochloric acid, Sodium hydroxide, water d / and.
0.5 ml – syringes, glass containers 1 ml (5) – trays, plastic (2) – packs cardboard.
Pharmacological action
Antitromboticheskiy preparation. Synthetic selective inhibitor of activated factor X (Far). Antithrombotic activity is the result of selective inhibition of factor Xa, oposredovannogo antitrombinom III. By selectively binding to antithrombin III, fondaparinux sodium potentiates (about 300 time) initial neutralization of factor Xa by antithrombin III. Neutralization of Factor Xa interrupts the chain of coagulation and inhibits both thrombin formation, and thrombus formation. Fondaparinux sodium does not inaktiviruet thrombin (activated factor IIa) and no effect on platelets.
When applied in a dose of 2.5 mg Arixtra does not affect the results of conventional coagulation tests, such as PTT, activated clotting time (AВC) or prothrombin time / INR blood plasma, nor bleeding time or fibrinolytic activity. However, rare reports have been received about the lengthening of APTT in the use of fondaparinux in dosage 2.5 mg.
Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopenia type II.
Pharmacodynamics / pharmacokinetics of fondaparinux is determined by its concentration in plasma, expressed in terms of anti-Xa-factorial Activity. To gauge assessment of anti-Xa activity can be used only fondaparinux, not suitable for this international standard heparin or low molecular weight heparins. This calibration is an expression of the concentration of fondaparinux in mg fondaparinux calibration / l.
Pharmacokinetics
Absorption
After s / c administration of fondaparinux sodium completely and rapidly absorbed from the injection site (absolute bioavailability 100%). After a single s / c injection dose 2.5 mg to young healthy volunteers Cmax in plasma achieved through 2 hours after administration and was on average 0.34 mg / l. Concentrations in plasma, constituting half of the above Cmax, achieved through 25 minutes after administration.
In healthy elderly pharmacokinetics of fondaparinux is linear in the range of doses 2-8 mg p /. When administered 1 time / day Css achieved through 3-4 day, while the Cmax and the increase in AUC 1.3 times.
The mean pharmacokinetic parameters of fondaparinux in equilibrium patients, substitutional undergoing hip surgery and received a dose of Arixtra 2.5 mg / day, We were: Cmax – 0.39 mg / l (31%), Tmax – 2.8 no (18%) and Cmin – 0.14 mg / l (56%).
Elderly patients, underwent surgery for hip fracture and treated with a dose Arikstra 2.5 mg / day, fondaparinux concentrations at steady state is: Cssmax – 0.50 mg / l (32%), Cssmin – 0.19 mg / l (58%).
Patients with symptoms of deep vein thrombosis or pulmonary embolism conducted Arixtra dose adjustment based on body weight: birth weight less than 50 kg dosed 5 mg, body weight 50-100 mg – 7.5 mg, body weight more 100 kg – 10 mg. This correction dose provided similar Cmax and Cmin all weight groups.
Distribution
In healthy adults, after n / a or / in the fondaparinux distributed in such a way, that much of it is in the blood and only a small amount of – in liquid ekstravenoznoy. Vd is 7-11 l. In vitro fondaparinux highly (no less 94%) specifically binds to the protein ATIII. Binding of fondaparinux with other plasma proteins (incl. with platelet factor IV and erythrocytes) insignificantly.
Metabolism
In vivo metabolism of fondaparinux has not been studied, tk. in patients with normal renal function, most of the administered dose is excreted unchanged in the urine.
Deduction
Fondaparinux is derived mainly kidneys unchanged. In healthy people, 64-77% the dose is excreted in the urine within 72 no. T1/2 is about 17 h in young healthy volunteers and about 21 no – elderly healthy subjects. In patients with normal renal function, the average clearance of fondaparinux 7.82 ml / min.
Pharmacokinetics in special clinical situations
In patients with renal insufficiency elimination of fondaparinux is slower, tk. it is mainly excreted by the kidneys in unchanged form. Patients, received prophylactic treatment after surgery for hip fracture or hip replacement, total clearance of fondaparinux on 25% lower with mild renal insufficiency (CC 50-80 ml / min), on 40% lower with moderate renal failure (CC 30-50 ml / min) and 55% lower with severe renal insufficiency (CC less than 30 ml / min), compared with patients with normal renal function. The values of the final T1/2 They were at moderate renal insufficiency 29 no, In severe – 72 no.
A similar relationship between fondaparinux clearance and severity of renal failure was observed in patients with deep vein thrombosis. The pharmacokinetic model used data on patients with CC less 23.5 ml / min, underwent surgery on the lower limbs and treated with fondaparinux. As a result of pharmacokinetic modeling has been shown, the use of fondaparinux in patients with CC on 20 to 30 ml / min at a dose 1.5 mg per day, or 2.5 mg a day corresponds to that in patients with mild to moderate renal impairment (CC 30-80 ml / min), receiving a drug dose 2.5 mg / day.
Due to the limitations of the currently available data, Arixtra should not be used in patients with severe renal insufficiency.
It is believed, that the concentration of free plasma fondaparinux does not change with mild to moderate liver dysfunction, Therefore, by adjusting the dose pharmacokinetics in these patients is not necessary. After a single s / c administration of fondaparinux in patients with impaired liver function moderate (The functional class according to Child-Pugh classification), Cmax and AUC values were down 22-39% compared to patients with normal liver function. Reducing the concentration of fondaparinux in plasma is explained by a decrease in binding to antithrombin III due to reduced levels of this enzyme in plasma in patients with impaired liver function, thereby increasing the kidney excretion fondaparinux. The pharmacokinetics of fondaparinux when severe hepatic impairment has not been studied.
Studies on the use of fondaparinux sodium in children and adolescents under the age of 17 years has not been.
Patients over the age of 75 years excretion fondaparinux slows. When administered at a dose of fondaparinux 2.5 mg prophylactically after surgery for hip fracture or hip replacement total clearance of fondaparinux was approximately 25% less than in patients over the age of 75 years compared to patients younger than 65 years. A similar relationship between fondaparinux clearance and age was observed in patients with deep vein thrombosis.
When correcting doses according to body weight there was no difference in the pharmacokinetics according to gender.
Planned research pharmacokinetic differences in individuals of different race has not been. But, test, conducted in healthy people of Asian descent (Japan), We found no difference in the pharmacokinetic profile compared to that in healthy individuals of the white race. There was no difference in the clearance of the drug between patients and blacks evropioidnoy, borne orthopedic surgery.
In patients weighing less than 50 kg total clearance of fondaparinux reduced by about 30%.
Testimony
- Prevention of venous thromboembolic events in patients, exposed “big” orthopedic surgery of the lower limbs (incl. when hip fractures, including extended prophylaxis in the postoperative period; surgery to replace a knee joint; replacement surgery of the hip joint);
- Prevention of venous thromboembolic events in patients, undergoing abdominal surgery and having the risk of thromboembolic events;
- Prevention of venous thromboembolic events in patients, with a high risk of complications, which shows a prolonged bed rest during the acute phase of the disease;
- Treatment of acute deep vein thrombosis;
- Treatment of acute pulmonary embolism;
- Treatment of acute coronary syndrome, which is a manifestation of unstable angina or myocardial infarction without ST segment elevation, in order to prevent cardiovascular death, myocardial infarction or refractory ischemia;
- Treatment of acute coronary syndrome, which it is a manifestation of myocardial infarction with ST-segment elevation in order to prevent death, re-myocardial infarction patients, receiving thrombolytic therapy or patients, initially did not receive reperfusion therapy.
Dosage regimen
N / a drug is introduced alternately in the left and the right anterolateral and left and right posterolateral abdominal wall. To prevent loss of the drug should not remove air bubbles from the pre-filled syringe prior to injection. The needle should enter the entire length perpendicular to the fold of skin, sandwiched between the thumb and forefinger; a fold of skin is not decompress during the introduction of.
The drug Arixtra should be used only under medical supervision. The patient is allowed to conduct their own s / c injection only if the doctor deems it necessary, followed by mandatory supervision of a doctor and only after proper training technique of s / c injection.
The on / in the introduction (the first dose only in patients with myocardial infarction ST-segment elevation) drug is introduced into the catheter in its original form or in dilution with small amounts 0.9% sodium chloride solution (25 ml or 50 ml). To prevent loss of the drug should not remove air bubbles from the prefilled syringe before injection. After injection, the catheter should be flushed with a sufficient amount of saline to ensure delivery of the full dose. When administered using a mini-containers infusion should be performed for 1-2 m.
Prevention of venous thromboembolic events
Orthopedic and abdominal surgery: the recommended dose of Arixtra 2.5 mg p / 1 time / day after surgery.
The initial dose is administered not earlier, than 6 hours after the completion of the transaction subject to a wealthy hemostasis.
The course of treatment lasts for a period of increased risk of venous thromboembolic events, typically to transfer the patient to outpatient treatment, no less 5-9 days. Experience shows, that for patients, exposed surgery for hip fracture, duration of the period of increased risk of venous thromboembolic complications exceeds 9 days. For such patients should decide to extend the prophylactic use Arixtra up 24 days.
Patients with high risk for thromboembolic complications: the recommended dose of Arixtra 2.5 mg p / 1 time / day. The duration of treatment in this case is from 6 to 14 days.
Treatment of acute deep vein thrombosis and acute pulmonary embolism: the recommended dose of Arixtra for the p / to the introduction 1 time / day is to Patients weighing less than 50 kg – 5 mg; to patients with a body weight 50-100 kg – 7.5 mg; to patients weighing more 100 kg – 10 mg.
Duration of treatment is at least 5 days. Treatment should be stopped not earlier, what will be possible to switch to adequate therapy with oral anticoagulants (MHO values from 2 to 3). It is also necessary as soon as possible to add to the treatment of vitamin K antagonists, usually, not later 72 no. Typically, course duration is from ARIXTRA 5 to 9 days.
Treatment of unstable angina / myocardial infarction without ST segment elevation: The recommended dose is 2.5 mg p / 1 time / day. Treatment should begin as soon as possible after diagnosis and continued for 8 days or until the patient is discharged.
To minimize the risk of bleeding elective percutaneous coronary intervention (PCI/PCI) It should be possible not earlier, than 24 h after the last dose of fondaparinux. If CHKB held less than 6 h after the last dose of ARIXTRA, should reduce the dose of unfractionated heparin (if applicable).
Time resumption administration Arixtra after catheter removal should be determined based on the patient's clinical status. In clinical studies of fondaparinux treatment resumed not earlier, than 2 hours after removal of the catheter.
At step coronary artery bypass grafting (AKS) Arikstru, possibly, not appointed within 24 hours prior to surgery and for 48 h after CABG.
Treatment of myocardial infarction with ST-segment elevation: The recommended dose is 2.5 mg 1 time / day. The first dose was administered on / in, all subsequent - n / a. Treatment should begin as soon as possible after diagnosis and continued for 8 days or until the patient is discharged.
To minimize the risk of bleeding should be planned CHKB, possibly, no earlier than 24 h after the last dose of fondaparinux. If CHKB held less, than 6 h after the last dose of ARIXTRA, should reduce the dose of unfractionated heparin (if applicable).
Time resumption administration Arixtra after catheter removal should be determined based on the patient's clinical status. In clinical studies of fondaparinux treatment resumed not earlier, than 2 hours after removal of the catheter.
At step AKS Arikstru, possibly, not appointed within 24 hours prior to surgery and for 48 h after CABG.
To patients impaired liver function Arixtra dose adjustment is not required. Patients with severe hepatic insufficiency Arixtra should be used with caution.
In patients with impaired renal function in QA > 30 ml / min at Prevention of venous thromboembolism dose adjustment is not required. In of patients with CC 20 to 30 ml / min, as well as in those patients, which benefits from the use of fondaparinux outweigh the risks of its use, The recommended dose is 1.5 mg daily or 2.5 mg every 48 no.
Patients, undergoing surgery, you must comply strictly with the time of the first dose of ARIXTRA.
At the treatment of venous thromboembolism in Patients with CC ≥ 30 ml / min Arixtra dose adjustment is not required. Patients with CC < 30 ml / min appoint fondaparinux should not be.
Arixtra should be used with caution in elderly patients (senior 75 years), tk. with age may be reduced kidney function. In elderly patients, undergoing surgery, you must comply strictly with the time of the first dose of ARIXTRA.
In Patients weighing less than 50 kg there is a risk of bleeding. During the surgical intervention in these patients must be strictly observed during administration of the first dose of ARIXTRA.
Side effect
The frequency of adverse reactions is represented by the following gradation: Often (>1/10), often (>1/100, <1/10); sometimes (>1/1000, <1/100); rarely (>1/10 000, <1/1000); rarely (<1/10 000).
From the hematopoietic system: often – anemia, bleeding (various localization, including rare cases of intracranial / intracerebral and retroperitoneal bleedings), purpura; sometimes – thrombocytopenia, thrombocythemia, changes in platelet, coagulation disorders.
Metabolism: rarely – kaliopenia.
CNS: sometimes – headache, rarely – anxiety, confusion, dizziness, drowsiness, loss of consciousness.
Cardio-vascular system: rarely – gipotenziya.
The respiratory system: rarely – breathlessness, cough.
From the digestive system: sometimes – nausea, vomiting, violation of liver function tests, increase in liver enzymes; rarely – stomach ache, dyspepsia, gastritis, constipation, diarrhea, elevation of serum bilirubin.
Dermatological reactions: sometimes – rash, itch, discharge from the wounds.
Other: often – swelling; sometimes – fever; rarely – postoperative wound infection, chest pain, pain in the legs, feeling tired, flushing of the face (tides), allergic reactions, injection site reactions.
These adverse reactions should be considered taking into account the clinical situation.
Contraindications
- Active, clinically significant bleeding;
- Acute bacterial endocarditis;
- Severe renal insufficiency (CC<30 ml / min);
- Hypersensitivity to the drug.
Not recommended Arixtra used immediately before and during primary percutaneous coronary intervention (ЧKB) in patients with myocardial infarction with ST-segment elevation. Monotherapy Arixtra is not recommended in patients with myocardial infarction without ST segment elevation and ST-segment elevation in the non-primary PCI. In such cases, you should evaluate the possibility of the combined purpose of unfractionated heparin. The available clinical data on the combined use of fondaparinux and UFH during non-primary PCI is limited.
FROM caution Arixtra should be used, like other anticoagulants, in patients with an increased risk of bleeding, such as congenital or acquired coagulation disorders in the form of bleeding, gastric ulcer and duodenal ulcer in the acute stage, after recently suffering an intracranial hemorrhage, soon after surgery on the brain or spine, or eye surgery, with severe hepatic dysfunction. Increased risk of bleeding during treatment with anticoagulants are: Patients older 75 years, Patients weighing less than 50 kg, patients with mild renal insufficiency (CC less than 50 ml / min). In the appointment of ARIXTRA patients, referred to at-risk groups, Caution is advised.
FROM caution Arikstra should be used in combination with other drugs, increase the risk of bleeding (eg, with inhibitors of GPIIb / IIIa, or thrombolytic) in the treatment of unstable angina or myocardial infarction without ST segment elevation myocardial infarction and ST-segment elevation.
Pregnancy and lactation
Accumulated to date data on the use during pregnancy are insufficient Arixtra. Arixtra should not be administered during pregnancy except in cases, when the intended benefits to the mother outweighs the potential risk to the fetus.
Unknown, whether fondaparinux is allocated with breast milk in humans. If necessary, use during lactation should stop breastfeeding.
IN experimental studies found, that fondaparinux is excreted in breast milk of lactating rats have.
Cautions
Arixtra is intended only for p / and / in (starting dose in patients with myocardial infarction with ST-segment elevation) applications. Do not use the / m!
We do not recommend the use of fondaparinux immediately before and during the primary CHKB in patients with myocardial infarction with ST-segment elevation.
Monotherapy fondaparinux is not recommended in patients in unstable angina and myocardial infarction without ST segment elevation, and myocardial infarction with ST-segment elevation after CHKB, should evaluate the possibility to combine the appointment unfractionated heparin. The available clinical data on the combined use of fondaparinux and unfractionated heparin are limited.
The frequency of the incidence of major bleeding in patients, prinimavshih fondaparinux for 6-24 hours prior to percutaneous coronary intervention and the appointment of an average dose of unfractionated heparin 8000 ME, estimated in 2%. Patients, received the last dose of fondaparinux less, than 6 h to non-primary CHKB and medium-dose unfractionated heparin 5000 ME, estimated in 4.1%.
In controlled studies, there was low, but an increased risk of catheter thrombosis during non-primary CHKB monotherapy fondaparinux, compared to the active control. The frequency of blood clots in the guiding catheter in the non-primary CHKB in patients with unstable angina and myocardial infarction without ST segment elevation was 1% Fondaparinux at primenenii, compared with 0.3% the application of enoxaparin; in primary PCI in patients with myocardial infarction with ST-segment elevation in the application of fondaparinux – 1.2%, compared to the control - 0%.
The prevention and treatment of venous thromboembolism drugs, increase the risk of bleeding, should not be administered in conjunction with Arixtra, except for vitamin K antagonist, used in the treatment of venous thromboembolic complications. If necessary, a combination therapy, it should be under strict control.
The prevention of venous thromboembolism after surgery must be strictly observed during administration of the first dose of ARIXTRA. This dose should be administered no earlier, than 6 hours after the operation, Only after the final hemostasis. Appointment of ARIXTRA earlier than 6 h may be associated with an increased risk of major bleeding. For high-risk groups include patients older 75 years, Patients weighing less than 50 kg, patients with mild renal insufficiency (CC < 50 ml / min).
When using Arixtra concurrently with the spinal / epidural anesthesia or lumbar puncture can not exclude the possibility of epidural or spinal hematoma, which can lead to long-term or permanent paralysis. The risk of these rare events may be increased with the use of permanent postoperative epidural catheters or simultaneous administration of other drugs, affecting hemostasis.
Elderly patients are more at risk of bleeding, than the rest of the population. As renal function generally decreases with age, elderly patients may decrease the clearance of fondaparinux and consequently an increase in exposure. Therefore, elderly patients Arixtra should be used with caution.
Patients weighing less than 50 kg higher risk of bleeding. Withdrawal of fondaparinux decreases with decreasing body weight. In these patients, Arixtra should be used with caution.
About 70% fondaparinux is excreted unchanged in the kidneys. Time clearance of fondaparinux increases with the severity of renal dysfunction and may increase the risk of bleeding. In patients with impaired renal function, especially in QC < 30 ml / min, increased risk of major bleeding and venous thromboembolism.
Clinical data on the use of fondaparinux in patients with CC < 20 ml / min insufficiently, therefore, use of the drug Arixtra for the prevention of venous thromboembolism in these patients is not recommended. Clinical data on the use of fondaparinux in patients with CC < 30 ml / min insufficiently, therefore, use of the drug Arixtra for the treatment of venous thromboembolism in these patients is not recommended.
There is limited clinical data on the use of fondaparinux in patients with unstable angina and myocardial infarction without ST segment elevation, as well as myocardial infarction with ST-segment elevation, with QC 20-30 ml / min, so being able to use in these patients is estimated in terms of the benefit / risk ratio. Fondaparinux is not recommended for patients with CC < 20 ml / min.
In severe hepatic dysfunction due to deficiency of clotting factor increases the risk of bleeding, ARIXTRA is therefore used in these patients with caution.
Effects fondaparinux not associated with platelet factor IV and do not affect the reaction in the plasma of patients with type II thrombocytopenia geparinindutsirovannoy. Arixtra should be used with caution in patients with heparin-induced thrombocytopenia history. So far, no specific clinical studies conducted to evaluate the efficacy and safety Arikstra patients with heparin-induced thrombocytopenia type II.
It was received rare reports of the development of heparin-induced thrombocytopenia in patients, poluchavshih fondaparinux. A significant association between the use of the drug and the development of thrombocytopenia is not installed.
Injectable solutions should use to visually monitor the absence of particulate matter and discoloration.
P / injection should be performed in the same manner, as with a conventional syringe.
Arikstra prefilled syringes were developed using an automatic protection system for preventing damage to the needle after injection.
With unused preparations and wastes should be treated in accordance with the local regulations.
Use in Pediatrics
The efficacy and safety of ARIXTRA at children and adolescents under the age of 17 years hitherto not installed.
Effects on ability to drive vehicles and management mechanisms
Arixtra Effect on ability to drive vehicles and classes of potentially hazardous activities is not known.
Overdose
Symptoms: bleeding.
Treatment: removal of the drug, examinee. Perhaps the use of surgical hemostasis, replenishment of blood loss, transfusion of fresh frozen plasma, plasmapheresis.
Drug Interactions
Fondaparinux does not inhibit cytochrome P450 isozymes system(CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 и CYP3A4) in vitro. Therefore, do not expect Arixtra interaction with other drugs at suppressing metabolism, mediated these isoenzymes, live.
Since the binding of fondaparinux to plasma proteins, isklyucheniem for antithrombin III, insignificantly, not be expected to interact with other drugs at the binding sites with plasma protein.
In clinical studies, fondaparinux, It was shown, his co-administration with oral anticoagulants (varfarinom), antiplatelet (acetylsalicylic acid), NSAIDs (piroksikamom) and serdechnыmi glikozidami (digoksinom), It did not affect the pharmacokinetics of fondaparinux. Fondaparinux does not affect our activity has warfarin, no bleeding time during treatment with acetylsalicylic acid or piroxicam, neither the pharmacokinetics of digoxin in equilibrium.
In the absence of data on the compatibility of the solution Arixtra should not be mixed with other drugs.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at temperature from 15 ° to 25 ° C; Do not freeze. Shelf life - 2 year.
