Fragmin 10000 IU (anti-Xa)/ml 1 ml ampule 10 pcs

Pharmacotherapeutic group: anticoagulant
means of direct action
ATX V01AV04 code
Pharmacological properties
Characteristic.
Dalteparin sodium low molecular weight heparin is selected in the process of controlled depolymerization (with nitrous acid) sodium heparin from intestinal mucosa pigs and subjected to further purification using ion exchange chromatography. The preparation consists of a sulfated polysaccharide chains having an average molecular weight of 5000 daltons; with 90% having a molecular weight of from 2000 to 9000 Daltons; degree of sulphation – from 2 to 2.5 per disaccharide
.
Pharmacodynamics
Dalteparin sodium through plasma antithrombin inhibits the activity of factor Xa and thrombin. Dalteparin sodium anticoagulant effect is primarily due to inhibition of factor Xa; at the time of blood clotting medication affects slightly. Compared with dalteparin sodium heparin has little effect on platelet adhesion and thus has minimal effect on primary hemostasis.
Pharmacokinetics.
The half-life after / in the preparation – 2 hours after subcutaneous administration – 3-5 hours. The bioavailability after subcutaneous administration of about 90%; The pharmacokinetic parameters are independent of dose.
In patients with uremia half-life of the drug is increased. Dalteparin sodium is derived primarily via the kidney, but the biological activity of the fragments that are excreted by the kidneys, poorly understood. The urine is determined by at least 5% of the anti-Xa activity. Clearance anti-Xa activity dalteparin from the plasma after a single intravenous administration as a bolus at a dose of 30 and 120 ME (anti-Xa) / kg averaged 24.6 ± 5.4 and 15.6 ± 2.4 ml / h / kg, respectively, and elimination half-life – 1.47 ± 0.3 and 2.5 ± 0.3 h.
Special groups
Hemodialysis – In patients with chronic renal failure receiving hemodialysis, the half-life of anti-Xa activity following a single intravenous administration of dalteparin at a dose of 5000 ME was 5.7 ± 2.0 h and was significantly higher than in healthy volunteers. Accordingly, such patients can expect a more pronounced accumulation of the drug.

Active substance:
Dalteparin sodium

Manufacturer

Pfizer, USA

Composition

Active ingredient: 2500 dalteparin sodium ME (anti-Xa) / 0,2ml, 5000 ME (anti-Xa) / 0,2ml, 10000 ME (anti-Xa) / ml, 7,500 ME (anti-Xa) / 0 Zml 10000 ME (anti-Xa) / 0,4ml, 12500 ME (anti-Xa) / 0.5 ml, 15000 ME (anti-Xa) / 0,6ml 18000 and ME (anti-Xa) / 0,72ml respectively.
Excipients: water for injection; if necessary (to adjust pH) – hydrochloric acid or sodium hydroxide q.s. (For 2,500 doses ME (anti-Xa) / 0,2ml, 5000 ME (anti-Xa) / 0,2ml 10000 and ME (anti-Xa) / ml) and sodium chloride (for 2500 doses ME (anti-Xa) / 0,2ml 10000 and ME (anti-Xa) / ml).

Indications

Prevention of thrombosis, prevention of thromboembolism, angina, prevention of acute myocardial infarction

• Treatment of acute deep vein thrombosis and pulmonary embolism;
• prevention of blood clotting in the extracorporeal blood during dialysis or hemofiltration in patients with acute or chronic renal failure;
• the prevention of thrombus formation during surgical procedures;
• prevention of thromboembolic complications in patients with therapeutic diseases in the acute phase and reduced mobility (including the conditions requiring bed rest);
• unstable angina and myocardial infarction (non-Q-wave on the ECG),
• long-term treatment (up to 6 months) in order to prevent recurrence of venous thrombosis and pulmonary thromboembolism in patients with cancer.

Contraindications

• Hypersensitivity to dalteparin sodium or other low molecular weight heparin and / or heparin;
• immune thrombocytopenia (heparin-induced history or suspicion of its presence);
• bleeding (clinically significant, for example, from the gastrointestinal tract against the background of gastric ulcers and / or duodenal ulcer, intracranial hemorrhage);
• The expressed disturbances of the blood coagulation system;
• bacterial endocarditis;
• recent injuries or surgery on the central nervous system, bodies of sight and / or hearing;
• In connection with the increased risk of bleeding, high doses of Fragmin (eg, for the treatment of acute deep vein thrombosis, pulmonary embolism, unstable angina and myocardial infarction without Q-wave on an electrocardiogram) can not be used in patients who are planned for spinal or epidural anesthesia or other procedures involving a lumbar puncture.

With caution
High doses of Fragmin (e.g., for treatment of acute deep venous thrombosis, pulmonary embolism, unstable angina and myocardial infarction without Q-wave on the electrocardiogram) may be used with caution in patients with early postoperative period.
Caution should be exercised in the appointment of Fragmin in patients with an increased risk of bleeding; this group includes patients with thrombocytopenia, platelet dysfunction, severe hepatic or renal failure, uncontrolled hypertension, hypertensive or diabetic retinopathy.

Side effects

The following side effects are noted (on average 1% of patients) bleeding, hematoma at the injection site, reversible non-immune thrombocytopenia, pain at injection site, allergic reactions, and transient increase in “liver” transaminases (ACT, ALT). It reported on several cases of immune thrombocytopenia (with or without thrombotic complications), as well as skin necrosis cases, anaphylactic reactions, development of spinal or epidural hematoma, peritoneal and intracranial bleeding, some of which were fatal.

How to accept, acceptance rate and dosage

Fragmin should not be administered intramuscularly!
acute deep vein thrombosis and treatment of pulmonary embolism
Fragmin administered subcutaneously 1-2 times a day. Thus it is possible immediately to begin therapy indirect anticoagulants (vitamin K antagonists). Such combination therapy should be continued for as long as the prothrombin ratio reaches a therapeutic level (usually it is not earlier than 5 days). Treatment of patients in an outpatient setting may be carried out in the same doses, which are recommended in the treatment in a hospital.

• Introduction 1 per day – a dose of 200 IU / kg body weight administered subcutaneously. A single daily dose should not exceed 18000 ME. Monitoring of anticoagulation activity of the drug may be dispensed with.


• Introduction 2 times a day – 100 IU / kg subcutaneously 2 times a day. Monitoring of anticoagulant activity can be omitted, but it should be borne in mind that it may be required in the treatment of specific patient populations (see. “Special Instructions” section). Recommended maximum plasma concentration of the drug should be 0,5-1 ME anti-Xa / mL.

Prevention of clotting in the extracorporeal circulation system during hemodialysis or hemofiltration
Fragmin be administered intravenously (w / w), by dosing regimen of the following.

• Patients with chronic renal failure, or patients without the risk of bleeding.

Such patients usually require a slight adjustment of dose, and because the majority of patients there is no need to carry out frequent monitoring of anti-Xa levels. When administered at the recommended doses hemodialysis time is usually achieved plasma level equal to 0,5 -1 ME anti-Xa / ml.

If the duration of hemodialysis or haemofiltration not more than 4 hours – / jet at 30-40 IU / kg body weight, followed by I / drip of 10-15 IU / kg / hour, either singly / in bolus a dose of 5000 ME. If the duration of hemodialysis or haemofiltration over 4 hours – / jet at 30 – 40 IU / kg body weight, followed by I / drip of -15 to 10 IU / kg / h .

• Patients with acute renal failure or patients with high risk of bleeding

B / bolus -10 5 IU / kg body weight, followed by I / drip of 4-5 IU / kg / h. Patients who conducted hemodialysis for acute renal failure, the drug is characterized by a narrow therapeutic index than patients on chronic hemodialysis (in connection with what they need adequate monitoring of the level of anti-Xa). The recommended maximum plasma level should be 0.2 – 0.4 ME anti-Xa / ml).
Prevention of thrombosis in surgical interventions
Fragmin should be injected subcutaneously. Monitoring of anticoagulation activity, as a rule, it is not required. In applying the drug at the recommended dose maximum plasma concentration are from 0.1 to 0,4 ME anti-Xa / ml.

• When conducting operations in the general surgical practice
  
  
  
  • Patients at risk for thromboembolic complications – 2500 ME subcutaneously 2 hours before surgery, then after the operation – subcutaneously 2,500 IU / day (every morning) during the entire period, while the patient is on bed rest (usually 5-7 days ).
  • Patients with additional risk factors for thromboembolic events (eg, patients with malignant tumors) – Fragmin should be applied throughout the period, while the patient is on bed rest (usually 5-7 days or more).
    1. At the beginning of therapy the day before surgery: ME 5000 n / a the night before surgery, followed by the ME 5000 p / every evening after the operation.
    2. At the beginning of therapy to laziness of operation: 2500 ME n / k for 2 hours before surgery and 2500 ME n / k over 8-12 hours, but not earlier than 4 hours after the operation is completed. Then the next day every morning at 5000 ME administered s / c.
  
  
  
  


• When conducting orthopedic surgery (for example, in operations for hip replacement)
  Fragmin be administered for up to 5 weeks after surgery, by selecting one of the dosage regimens set forth below.
  1. At the beginning of therapy night before surgery: ME 5000 n / a night before surgery, then ME 5000 n / k every night after surgery.
  2. At the beginning of the therapy on the day of surgery: 2500 ME n / k for 2 hours before surgery and 2500 ME n / k over 8-12 hours, but not earlier than 4 hours after the operation is completed. Then the next day every morning – 5000 ME n / a.
  3. At the beginning of therapy after surgery: 2500 ME n / k after 4-8 hours after the operation, but not earlier than 4 hours after the operation is completed. Then the next day for ME 5000 p / day.

Prophylaxis of thromboembolic complications in patients with therapeutic diseases in the acute phase and reduced mobility (including the conditions requiring bed rest)
Fragmin should be injected subcutaneously 5000 ME once a day, usually within 12-14 days or longer (in patients with continuing limited mobility). Monitoring of anticoagulation activity, as a rule, it is not required.
Unstable angina and myocardial infarction (non-Q-wave on the electrocardiogram)
Monitoring of anticoagulation activity, as a rule, it is not required, but it should be borne in mind that it may be required in the treatment of specific patient populations (see. Section “Special Instructions”). The recommended maximum concentration of drug in plasma should be 0,5-1 ME anti-Xa / ml (simultaneously it is expedient to conduct therapy of acetylsalicylic acid in a dose of from 75 to 325 mg / day). Fragmin injected subcutaneously with 120 IU / kg body weight, every 12 hours. The maximum dose should not exceed 10,000 ME every 12 hours.
Therapy should be continued for as long as the patient’s clinical condition has become stable (usually not less than 6 days) or longer (at the discretion of the physician). Then, it is recommended to go long-term therapy in a constant dose of Fragmin until revascularization (percutaneous coronary intervention or bypass surgery). The total duration of therapy should not exceed 45 days.
Fragmin dose selected on the basis of sex, and weight of the patient:

• women weighing less than 80 kg and men weighing less than 70 kg should be administered ME 5000 n / k every 12 hours;
• women weighing 80 kg or more and male weighing 70 kg or more should be administered ME 7500 n / k every 12 hours.

Long-term treatment to prevent recurrence of venous thromboembolism in patients with cancer.

• 1 month
  Introduction 1 per day – 200 IU / kg subcutaneously. A single daily dose should not exceed 18000 ME.


• 2-6 months
  Introduction 1 times a day – a dose of about 150 IU / kg body weight subcutaneously, using a fixed dose syringes (see Table 1)

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Table 1. Determination of dose Fragmin depending on body weight for the duration of treatment 2 – 6 months.

Body weight, kg	The dose of Fragmin, ME
< 56	7500
57-68	10000
69-82	12500
83-98	15000
> 99	18000

 Thrombocytopenia – In case of thrombocytopenia, developed on a background of chemotherapy with a platelet count < 50,000 / mm application Fragmin should be suspended before the increase in the platelet count more than 50,000 / microliter. For platelet count of 50,000 / ml to 100,000 / microliter dose should be reduced by 17% -33% relative to the initial dose, depending on the patient body weight (Table. 2). When recovering the platelet count to a level > 100,000 / ml, the drug should be given the full dose.

Table 2. Reduction of Fragmin at a dose of thrombocytopenia 50000 / L-100000 / L.

Body weight, kg	The planned dose Fragmin, ME	Reduced dose Fragmin	Dose reduction,%
< 56	7500	5000	33
57-68	10000	7500	25
69-82	12500	10000	20
83-98	15000	12500	17
> 99	18000	15000	17

Renal failure – In case of significant renal failure, defined as a creatinine level exceeded 3-fold increase of the upper limit of normal, the dose of Fragmin should be adjusted so as to maintain a therapeutic level of 1 anti-Xa IU / ml (range 0.5-1.5 IU / ml), measured within 4-6 hours after administration dalteparin. If the level of anti-Xa, below or above the therapeutic range, Fragmin dose should be increased or reduced accordingly and, measurement of anti-Xa must be repeated after a new administration 3-4 doses. No dosage adjustment should be carried out anti-Xa to achieve a therapeutic level.

Storage conditions

Ampoules: at a temperature no higher than 30 ° C
Syringes: at a temperature no higher than 25 ° C
Keep out of the reach of children.

Active substance

Dalteparin sodium

Interaction

While the use of drugs affecting hemostasis, such as thrombolytic agents (alteplase, streptokinase, urokinase), oral anticoagulants, vitamin K antagonists, non-steroidal anti-inflammatory drugs (acetylsalicylic acid, indomethacin, etc.), As well as inhibitors of platelet function, anticoagulant effect Fragmin may be exacerbated (increased risk of bleeding).
Compatibility with intravenous fluids. Fragmin compatible with isotonic sodium chloride solution (9 mg / ml) and isotonic dextrose (50 mg / ml).

Special conditions

Fragmin should not be administered intramuscularly!
In carrying out neuraxial anesthesia (epidural / spinal anesthesia) or performing a lumbar puncture in patients receiving anticoagulant therapy, or who planned to carry out anticoagulation therapy with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at increased risk of developing an epidural or spinal hematoma, which in turn can lead to long-term or permanent paralysis. The risk of these complications increases when using permanent epidural catheters for administering analgesics, or the simultaneous use of drugs affecting hemostasis, such as non-steroidal anti-inflammatory drugs, inhibitors of platelet function and other anticoagulants. The risk also increases with injuries and after repeated epidural or lumbar puncture. In such cases, patients should be kept under constant surveillance for the early detection of abnormal neurological symptoms. In identifying neurological pathology demonstrated urgent intervention (decompression of the spinal cord).
There are no clinical data on the use of Fragmin in patients with pulmonary embolism who also noted circulatory disorders, hypotension or shock.
Require special attention patients whose treatment with Fragmin been a rapid development of thrombocytopenia, or thrombocytopenia with platelet counts less than 100,000 / ml. In such cases it is advisable to conduct in vitro test for anti-platelet antibodies in the presence of heparin or low molecular weight heparins. If the result of the in vitro test is positive or uncertain, or testing in general has not been made, the treatment of Fragmin should be discontinued (see. Section “Contraindications”). In the monitoring of anticoagulant activity of Fragmin is usually not necessary, however, it may be necessary in the treatment of specific groups of patients: children, patients with a body weight lower than normal or obese, pregnant women, and patients with an increased risk of bleeding or re-thrombosis. Blood samples for the analysis of Fragmin activity to be performed in the period when the maximum concentration of drug in plasma (3-4 hours after s / c injection).
To determine the activity of anti-Xa method of choice recognized laboratory tests, which use a chromogenic substrate. In this case the tests should not be used for determining activated partial thromboplastin time (APTT) and thrombin time as these tests are relatively insensitive to sodium dalteparin activity. Increasing doses of Fragmin to increase APTT may cause bleeding (see. The section “Overdose”).
AUs Fragmin, unfractionated heparin and other low molecular weight heparins are not equal, however replacing one other drug dose is required to make adjustments.
When using a multidose vial unused solution to be destroyed within 14 days after the first puncturing needle tube.

Pregnancy and lactation

In experiment Fragmin has no teratogenic action or foetotoxic. When used in pregnant women has not been revealed adverse effects on pregnancy and fetal and newborn health. In the application of Fragmin during pregnancy on the fetus risk of adverse effects is considered low.
However, since the possibility of adverse effects still can not be completely excluded, Fragmin can be administered during pregnancy only when there are clear indications that the expected benefits outweigh the potential risks. It not determined whether Fragmin in mother’s milk is released.

Overdose

Fragmin excessive dose may lead to hemorrhagic complications. In overdose in most cases possible bleeding of the skin and mucosa, gastrointestinal and urogenital tracts. decreased blood pressure, decreased hematocrit or other symptoms may be indicative of occult bleeding.
In the case of use of bleeding dalteparin sodium should be suspended to assess the severity of bleeding, and risk of thrombosis.
The anticoagulant effect can be eliminated Fragmin administration of protamine sulfate, which is a means of emergency treatment. 1 mg of protamine sulfate neutralizes part 100 ME (anti-Xa) sodium dalteparin (and. Is noted though complete neutralization induced increase in clotting time from 25 to 50% anti-Xa activity dalteparin sodium still remains).

Weight	0.051 kg
Expiration date	3 years. Do not use beyond the expiration date printed on the package.
Dosage form	injection and infusion