2010/09/21

Arixtra

Composition, structure and packing

Solution for Serial to introduce a transparent, colorless, without any visible mechanical inclusions.

1 syringe fondaparinux sodium 2.5 mg.

Excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water d / and.

Clinico-pharmacological group: anticoagulant direct action - a selective inhibitor of factor Xa.

Pharmacological action

Synthetic selective inhibitor of activated factor X (Xa). Antithrombotic activity is the result of selective inhibition factor Xa, mediated by antithrombin III. Selectively binding to antithrombin III, fondaparinux sodium potentiates (about 300 times) the original neutralizing factor Xa to antithrombin III. Neutralization of factor Xa interrupts the chain of coagulation and inhibits both thrombin formation and the formation of blood clots.

Fondaparinux sodium does not inactivate thrombin (activated factor IIa) and no effect on platelets. When applying a dose of 2.5 mg Arikstra not affect the results of conventional coagulation tests such as APTT, activated clotting time (AVC) or prothrombin time / INR in plasma, nor the bleeding time or fibrinolytic activity. However, rare reports have been received for the extension of APTT at the use of fondaparinux in a dosage of 2.5 mg.

Fondaparinux does not cross-reactions with the serum of patients with heparin-induced thrombocytopenia type II. Pharmacodynamics / pharmacokinetics of fondaparinux is determined by its concentration in plasma, expressed in terms of anti-Xa-factor activity. To gauge evaluation of anti-Xa activity of fondaparinux can be used only for this does not fit the international standard heparin or low molecular weight heparins. The result of this calibration is to express the concentration of fondaparinux in the calibration mg fondaparinux / liter.

Pharmacokinetics

Absorption

After sc administration fondaparinux sodium completely and rapidly absorbed from the injection site (absolute bioavailability of 100%). After a single sc injection of the drug at a dose of 2.5 mg to young healthy volunteers Cmax in plasma was achieved within 2 h after administration and averaged 0.34 mg / liter. Concentrations in plasma, constituting half of the above Cmax, were achieved within 25 min after injection. In healthy elderly pharmacokinetics of fondaparinux is linear in the range of doses of 2-8 mg of n / k.

When you enter 1 time per day Css achieved after 3-4 days, while Cmax and AUC values increased 1.3 times. Mean pharmacokinetic parameters of fondaparinux in a state of equilibrium in patients who had substitutsionnye operation on the hip joint and Arikstru receiving a dose of 2.5 mg / day were: Cmax - 0.39 mg / l (31%), Tmax - 2.8 h (18%) and Cmin - 0.14 mg / l (56%). In elderly patients, who underwent surgery for a broken hip and Arikstru receiving a dose of 2.5 mg fondaparinux concentration in the equilibrium state were: Cssmax - 0.50 mg / l (32%), Cssmin - 0.19 mg / l (58%).

Patients with symptoms of deep vein thrombosis or pulmonary embolism shall adjust the dose Arikstry, depending on body weight: birth weight less than 50 kg a dose of 5 mg, with body weight 50-100 mg - 7.5 mg in body weight over 100 kg - 10 mg. Such a dosage adjustment provided similar Cmax and Cmin in all weight groups.

Distribution

In healthy adults, after s / c or / in the introduction of fondaparinux distributed in such a way that most of it is in the blood and only a small amount - in ekstravenoznoy fluid. Vd was 7.11 liters. In vitro fondaparinux in a high degree (not less than 94%) specifically bind to ATIII. The binding of fondaparinux with other plasma proteins (including those with platelet factor IV, and red blood cells) is negligible.

Metabolism

In vivo metabolism of fondaparinux has not been studied, because in patients with normal renal function, most of the administered dose excreted unchanged in the urine.

Withdrawal

Fondaparinux is derived primarily by the kidneys unchanged. In healthy people, 64-77% of the dose excreted in the urine within 72 h. T1 / 2 approximately 17 h in young healthy individuals, and about 21 hours - in elderly healthy individuals. In patients with normal renal function, the average clearance of fondaparinux was 7.82 ml / min.

Pharmacokinetics in special clinical situations

In patients with renal insufficiency elimination of fondaparinux is slower, because it is mainly derived kidneys unchanged.

Patients who received prophylactic treatment after surgery for hip fracture or hip replacement, total clearance of fondaparinux is 25% lower in patients with renal insufficiency of mild (CC 50-80 ml / min), 40% lower in patients with renal insufficiency moderately (CC 30-50 ml / min) and 55% lower in patients with renal failure severe (CC less than 30 ml / min), compared with patients with normal renal function. Values of end-T1 / 2 were in renal insufficiency moderately 29 h, severe - 72 hours a similar relationship between fondaparinux clearance and the severity of renal failure was observed in the treatment of patients with deep vein thrombosis. In the pharmacokinetic model used data on patients with CC than 23.5 ml / min, underwent surgery on the lower extremities and treated with fondaparinux.

As a result, pharmacokinetic modeling, it was shown that the use of fondaparinux in patients with CC from 20 to 30 ml / min at a dose of 1.5 mg daily or 2.5 mg every other day corresponds to that in patients with mild to moderate renal dysfunction (CC 30-80 ml / min) receiving the drug at a dose of 2.5 mg / day. Because of the limited available to date data Arikstra should not be used in patients with renal failure and severe.

It is believed that the concentration of free fondaparinux in plasma does not change with mild to moderate liver problems, so on the basis of pharmacokinetics in the dose adjustment in patients with impaired liver function is not needed. After a single sc administration of fondaparinux in patients with hepatic impairment moderate (functional class in the classification of Child-Pugh), Cmax and AUC decreased by 22-39% compared with patients with normal liver function. Reducing the concentration of fondaparinux in plasma is attributable to reduced binding to antithrombin III due to the reduced level of this enzyme in plasma in patients with impaired liver function, resulting in increased excretion of fondaparinux kidneys.

The pharmacokinetics of fondaparinux with severe hepatic insufficiency has not been studied. Studies on the Application of fondaparinux sodium in children and adolescents under the age of 17 years was conducted. Patients aged over 75 years of excretion fondaparinux slows. With the introduction of fondaparinux at a dose of 2.5 mg as a prophylactic measure after surgery for hip fracture or hip replacement total clearance of fondaparinux was approximately 25% lower in patients aged over 75 years, compared with patients under the age of 65 years. A similar relationship between fondaparinux clearance and age was observed in patients with deep vein thrombosis.

When dose adjustment according to body mass was not detected differences in the pharmacokinetics of sex. Planned studies of pharmacokinetic differences among persons of different race was conducted. However, tests conducted with the participation of healthy persons of Asian origin (Japan), revealed no differences in the pharmacokinetic profile compared with that in healthy persons of the white race. There was no difference in clearance of the drug between patients evropioidnoy and blacks, had undergone orthopedic surgery. Patients weighing less than 50 kg total clearance of fondaparinux reduced by about 30%.

Statement
Prevention of venous thromboembolic complications in patients undergoing orthopedic surgery big in the lower extremities (including fractures of the hip joint, including the long-prevention in the postoperative period, surgery for the replacement of the knee joint; operations for the replacement of the hip joint);
prevention of venous thromboembolic complications in patients undergoing abdominal surgery and the risk for thromboembolic complications;
Prevention of venous thromboembolic complications in patients with high risk of complications, which shows a long bed rest during the acute phase of disease;
treatment of acute deep vein thrombosis;
treatment of acute pulmonary embolism;
treatment of acute coronary syndrome, a manifestation of which is unstable angina or myocardial infarction without ST segment elevation ST, with the aim of preventing cardiovascular death, myocardial infarction or refractory ischemia;
treatment of acute coronary syndrome, a manifestation of which is a myocardial infarction with ST-segment elevation with a view to preventing death, myocardial infarction patients receiving thrombolytic therapy or patients who initially did not receive reperfusion therapy.

Dosage regimen

N / a drug is introduced alternately in the left and right anterolateral and left and right zadnelateralnuyu abdominal wall. To avoid loss of the drug should not remove air bubbles from the pre-filled syringe before injection. Needle should enter the entire length perpendicular to the fold of skin, which is gripped between the thumb and forefinger, a fold of skin is not the payload during the entire administration. Arikstra drug should be used only under medical supervision. The patient is allowed to conduct the sc injection, only if a doctor deems it necessary, with a mandatory follow-up supervision of a physician and only after proper training techniques for sc injection.

When i / in the introduction (first dose only in patients with myocardial infarction-segment elevation ST) drug injected into the catheter in its original form or with dilution in small volume with 0.9% sodium chloride solution (25 ml or 50 ml). To avoid loss of the drug should not remove air bubbles from the pre-filled syringe before injection. After injection, the catheter should be flushed with plenty of saline to ensure delivery of a full dose of the drug. In the introduction to the use of mini-containers infusion should be held for 1-2 minutes. The drug is prescribed for adults.

Prevention of venous thromboembolic complications

Orthopedic and abdominal surgery: The recommended dose is 2.5 mg Arikstry n / a 1 time / day after surgery. The initial dose is introduced not earlier than 6 h after the operation is completed, subject to a wealthy hemostasis. The treatment lasts for a period of increased risk of venous thromboembolic complications, usually to transfer the patient to outpatient treatment, at least 5-9 days.

Experience shows that for patients undergoing surgery for a broken hip, the period of increased risk of venous thromboembolic complications than 9 days. For such patients should decide to extend the prophylactic use of Arikstry to 24 days. Patients with high risk of thromboembolic complications: the recommended dose is 2.5 mg Arikstry n / a 1 time per 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 Arikstry for sc administration 1 times / d is for patients weighing less than 50 kg - 5 mg for patients weighing 50-100 kg - 7.5 mg for patients with body weight over 100 kg - 10 mg.

The treatment duration is at least 5 days. Treatment should be terminated no earlier than would 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, as a rule, not later than 72 hours duration of the course Arikstry usually ranges from 5 to 9 days.

Treatment of unstable angina / myocardial infarction without ST segment elevation ST: The recommended dose is 2.5 mg sc 1 time / day. Treatment should begin as soon as possible after diagnosis and continue for 8 days or until the patient's discharge. To minimize the risk of bleeding planned PCI should be possible not earlier than 24 hours after the last dose of fondaparinux. If CHKB held less than 6 hours after the last dose Arikstry, should reduce the dose unfractionated heparin (if applicable).

Time of resumption of the introduction Arikstry after removal of the catheter should be determined on the basis of the clinical condition of the patient. In clinical studies of fondaparinux treatment was renewed not earlier than 2 h after catheter removal. When the operation of aorto-coronary bypass surgery (CABG) Arikstru, if possible, should not be administered within 24 hours before surgery and within 48 hours after CABG. Treatment of myocardial infarction segment elevation, ST: The recommended dose is 2.5 mg 1 time / day. The first dose is introduced into the I / O and all subsequent - n / k. Treatment should begin as soon as possible after diagnosis and continue for 8 days or until the patient's discharge.

To minimize the risk of bleeding routine H KB should be, if possible, no earlier than 24 hours after the last dose of fondaparinux. If CHKB held less than 6 h after the last dose Arikstry, should reduce the dose unfractionated heparin (if applicable). Time of resumption of the introduction Arikstry after removal of the catheter should be determined on the basis of the clinical condition of the patient.

In clinical studies of fondaparinux treatment was renewed no earlier than 2 hours after catheter removal. When conducting operations Arikstru CABG, if possible, should not be administered within 24 hours before surgery and within 48 hours after CABG. For patients with hepatic impairment dose adjustment Arikstry not required. Patients with severe hepatic insufficiency Arikstru be used with caution.

Patients with impaired renal function in QA> 30 ml / min in the prevention of venous thromboembolism dose adjustment is required. In patients with CC from 20 to 30 ml / min, as well as in those patients for whom the benefits of fondaparinux use outweigh the risks of its use, the recommended dose is 1.5 mg daily or 2.5 mg a day every 48 hours in patients undergoing surgery, must be strictly observed during the first dose Arikstry.

In the treatment of venous thromboembolism in patients with CC ≥ 30 ml / min Arikstry dose adjustment is required. Patients with CC <30 ml / min appoint fondaparinux should not be. Arikstru should be used with caution in elderly patients (older than 75 years), because with age may be reduced kidney function. In elderly patients undergoing surgery, should be strictly observed during the first dose Arikstry. In patients weighing less than 50 kg are at risk of bleeding.

In carrying out surgical intervention in these patients must be strictly observed during the first dose Arikstry.

Side effect

The frequency of adverse reactions is presented in accordance with the following scale: very often (> 1 / 10), frequently (> 1 / 100, <1> 1 / 1000, <1> 1 / 10 000, <1 / 1000); very rarely (<1 / 10 000).

On the part of the hemopoietic system: often - anemia, bleeding (various locations, including rare cases of intracranial / intracerebral hemorrhage, and retroperitoneal), purpura, and sometimes - thrombocytopenia, thrombocythemia, changes in platelet count, a violation of coagulation.

On the part of metabolism: rarely - hypokalemia.

From the side of the central nervous system: sometimes - headache, rare - anxiety, confusion, dizziness, drowsiness, loss of consciousness.

Since the cardiovascular system: rarely - hypotension.

On the part of the respiratory system: rarely - shortness of breath, cough.

On the part of the digestive system: sometimes - nausea, vomiting, a violation of indicators of liver function, increase in liver enzymes; rare - abdominal pain, dyspepsia, gastritis, constipation, diarrhea, elevated levels of bilirubin in the blood serum.

Dermatological reactions: sometimes - rash, itching, oozing wound.

Other: often - swelling, and sometimes - fever, rarely - postoperative wound infection, chest pain, leg pain, fatigue, flushing face (flushing), allergic reactions, reactions at the injection site. These adverse reactions should be considered in the light of the clinical situation.

Contraindications
active, clinically significant bleeding;
acute bacterial endocarditis;
renal failure, severe (CC <30 ml / min);
Hypersensitivity to the drug's components.

Not recommended Arikstru immediately before and during primary percutaneous coronary intervention (CHKB) in patients with myocardial infarction segment elevation, ST. Arikstroy monotherapy is not recommended in patients with myocardial infarction without ST segment elevation and ST-segment elevation in nepervichnom PCI. It should assess the possibility of combining appointment unfractionated heparins. Available clinical data on the combined use of fondaparinux and unfractionated heparin is limited in nepervichnom PCI.

Precautions should be applied Arikstru, like other anticoagulants, patients with increased risk of bleeding, such as congenital or acquired breach the blood coagulation system in the form of bleeding in the stomach ulcer and duodenal ulcer in acute phase, after recently transferred to intracranial hemorrhage, soon after surgical intervention on the brain or spinal cord, or eye operations in cases of severe liver problems. Increased risk of bleeding during treatment with anticoagulants include: patients older than 75 years, patients weighing less than 50 kg, patients with moderate renal insufficiency (CC less than 50 ml / min).

In appointing Arikstry patients classified into risk groups is recommended caution.

Precautions should be applied Arikstru in combination with other drugs that increase the risk of bleeding (eg, inhibitors of GPIIb / IIIa, or thrombolytic agents) in the treatment of unstable angina or myocardial infarction without ST segment elevation and myocardial segment elevation, ST.

Pregnancy and lactation

Experience to date data on the use Arikstry during pregnancy are insufficient. Arikstru should not be given during pregnancy except in cases where the intended benefits to the mother outweighs the potential risk to the fetus. It is not known 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 in lactating rats.

Application for violations of liver function

For patients with impaired liver function correction doses Arikstry not required. Patients with severe hepatic insufficiency Arikstru be used with caution.

Application for violations of renal function

For patients with impaired renal function, mild or moderate severity (spacecraft more than 30 ml / min) does not require dose adjustment Arikstry. In such patients undergoing surgery, must be strictly observed during the first dose Arikstry. Do not use this drug for renal failure, severe (CC <30 ml / min).

Cautions

Arikstra intended only for s / c and / in (starting dose in patients with myocardial infarction segment elevation, ST) use.

Do not use the / m! Do not use fondaparinux immediately before and during the primary CHKB in patients with myocardial infarction segment elevation, ST. Monotherapy with fondaparinux is not recommended in patients with unstable angina and myocardial infarction without ST elevation ST, and myocardial infarction with ST-segment elevation after CHKB should assess the feasibility of combining appointment unfractionated heparins. Available clinical data on the combined use of fondaparinux and unfractionated heparin is limited. Incidence of massive bleeding in patients receiving fondaparinux for 6-24 h before the percutaneous coronary intervention and the appointment of an average dose unfractionated heparin 8000 ME, estimated at 2%. Patients who received the last dose of fondaparinux less than 6 hours before nepervichnyh CHKB and the average dose unfractionated heparin 5000 ME, estimated at 4.1%. In controlled studies have reported a low but increased risk of catheter thrombosis during nepervichnogo CHKB monotherapy fondaparinux, compared with active control. The frequency of blood clots in catheters for conductive nepervichnom CHKB in patients with unstable angina and myocardial infarction without ST segment elevation was 1% when using fondaparinux, compared with 0.3% in the application of enoxaparin, with urgent PCI in patients with acute myocardial infarction with ST-segment elevation in use of fondaparinux - 1.2%, compared with the control - 0%.

Drugs that increase the risk of bleeding, should not be given together with Arikstroy, except for vitamin K antagonists, used in the treatment of venous thromboembolic complications. If necessary, combination therapy, it should be under strict control.

For the prevention of venous thromboembolic complications after surgical operations should strictly observe the time of the first dose Arikstry. This dose should be administered no earlier than 6 h after the operation is completed only after the final hemostasis. Appointment Arikstry earlier than 6 h may be associated with increased risk of severe bleeding. For high-risk groups include patients older than 75 years, patients weighing less than 50 kg, patients with moderate renal insufficiency (CC less than 50 ml / min).

In applying Arikstry simultaneously with spinal / epidural anesthesia or lumbar puncture can not be excluded possibility of epidural or spinal hematoma, which can lead to prolonged or permanent paralysis. The risk of these rare events may increase with postoperative use of permanent epidural catheters or the simultaneous administration of other drugs that affect on hemostasis.

Elderly patients are more prone to risk of bleeding than the rest of the population. Because renal function normally declines with age, elderly patients may decrease elimination of fondaparinux and consequently increase the exposure. Therefore Arikstru elderly patients should be used with caution.

Patients weighing less than 50 kg greater risk of bleeding. Derivation of fondaparinux decreases with decreasing body weight. In such patients Arikstru should be used with caution. About 70% of fondaparinux is excreted unchanged in the kidneys. Time elimination of fondaparinux decreases with increasing severity of renal dysfunction and may increase the risk of bleeding. Patients with impaired renal function, especially in spacecraft less than 30 ml / min, increases the risk of massive bleeding and venous thromboembolism.

Clinical data on the use of fondaparinux in patients with CC than 20 ml / min is insufficient, so the use of fondaparinux for the prevention of venous thromboembolism in these patients is not recommended. Clinical data on the use of fondaparinux in patients with creatinine clearance <30 ml / min is insufficient, so the use of Arikstry for the treatment of venous thromboembolism in these patients is not recommended.

There are limited clinical data on the use of fondaparinux in patients with unstable angina and myocardial infarction without ST segment elevation ST, as well as in myocardial infarction-segment elevation ST, with CC 20-30 ml / min, so the possibility of such patients is evaluated in terms of the ratio benefit / risk. Fondaparinux is not recommended for patients with CC than 20 ml / min.

In severe liver problems due to lack of blood coagulation factor increases the risk of bleeding, so use Arikstru in this patient should be cautious. Effects of fondaparinux is not associated with platelet FACT IV and shall not affect the plasma reaction in patients with geparinindutsirovannoy thrombocytopenia type II. Arikstru should be used with caution in patients with thrombocytopenia geparinindutsirovannoy history. So far, no specific clinical studies were conducted to study the efficacy and safety in patients with Arikstry geparinindutsirovannoy thrombocytopenia type II. Were received rare reports of the development geparinindutsirovannoy thrombocytopenia in patients treated with fondaparinux. No reliable connection between the use of the drug and the development of thrombocytopenia is not installed.

Injection solution should be to use a visual control of the absence of suspended particles and discolouration. P / K injections should be performed in the same way as with conventional syringe. Pre-filled syringes Arikstra were developed using an automatic needle protection system to prevent damage after the injection. Since the unused product and waste should be treated in accordance with local regulations.

Use in Pediatrics

Efficacy and safety of Arikstry in children and adolescents under the age of 17 years so far not been established.

Effects on ability to drive vehicles and management mechanisms

Influence Arikstry on ability to drive vehicles and occupations potentially hazardous activities are not known.

Overdose

Symptoms: bleeding.

Treatment: removal of preparation, examination of the patient. Perhaps the use of surgical hemostasis, supplementation of blood loss, transfusion of fresh plasma, plasmapheresis.

Drug Interactions

Fondaparinux does not inhibit isozymes of cytochrome P450 (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in vitro. Therefore, one should not expect Arikstry interaction with other drugs at the level of suppression of metabolism mediated by these isoenzymes, in vivo. Since the binding of fondaparinux to plasma proteins, except for antithrombin III, slightly, do not expect interaction with other drugs at the level of binding sites with blood plasma proteins.

In clinical trials, fondaparinux has been shown that his joint appointment with the oral anticoagulants, and (warfarin), antiagregantami (acetylsalicylic acid), NSAIDs (piroxicam) and cardiac glycosides (digoxin), no effect on the pharmacokinetics of fondaparinux.

Fondaparinux has no effect on the activity of warfarin, nor at the time of bleeding during treatment with acetylsalicylic acid or piroxicam, or on the pharmacokinetics of digoxin in the equilibrium state.

In the absence of data on the compatibility of the solution Arikstry should not be confused with other drugs.

Terms and Conditions of storage

The drug should be stored out of reach of small children at a temperature of 15 ° to 25 ° C Do not freeze. Shelf life - 2 years.