Universal reference book for medicines
Product name: FRAGMIN ® (FRAGMIN ® )

Active ingredient: dalteparin sodium

Type: Direct anticoagulant - low molecular weight heparin

Manufacturer: PFIZER MFG.
BELGIUM (Belgium) manufactured by Vetter Pharma-Fertigung (Germany)
Composition, form of production and packaging
The solution for IV and IV administration is
clear, colorless or with a yellowish tinge.

0.2 ml

dalteparin sodium 2500 IU (anti-Xa)

Excipients: sodium chloride, sodium hydroxide or hydrochloric acid qs, water d / u.

0.2 ml - single-dose glass syringes (5) - blisters (2) - cardboard packs.

The solution for IV and IV administration is clear, colorless or with a yellowish tinge.

0.2 ml

dalteparin sodium 5000 IU (anti-Xa)

Excipients: sodium hydroxide or hydrochloric acid qs, water d / u.

0.2 ml - single-dose glass syringes (5) - blisters (2) - cardboard packs.

The solution for IV and IV administration is clear, colorless or with a yellowish tinge.

0.3 ml

dalteparin sodium 7500 IU (anti-Xa)

Auxiliary substances: water d / and.

0.3 ml - single-dose glass syringes (5) - blisters (2) - cardboard packs.

The solution for IV and IV administration is clear, colorless or with a yellowish tinge.

0.4 ml

dalteparin sodium 10,000 IU (anti-Xa)

Auxiliary substances: water d / and.

0.4 ml - single-dose glass syringes (5) - blisters (1) - cardboard packs.

The solution for IV and IV administration is clear, colorless or with a yellowish tinge.

1 ml

dalteparin sodium 10,000 IU (anti-Xa)

Excipients: sodium chloride, sodium hydroxide or hydrochloric acid qs, water d / u.

1 ml - ampoules (10) - packs of cardboard.

The solution for IV and IV administration is clear, colorless or with a yellowish tinge.

0.5 ml

dalteparin sodium 12 500 IU (anti-Xa)

Auxiliary substances: water d / and.

0.5 ml - single-dose glass syringes (5) - blisters (1) - cardboard packs.

The solution for IV and IV administration is clear, colorless or with a yellowish tinge.

0.6 ml

dalteparin sodium 15,000 IU (anti-Xa)

Auxiliary substances: water d / and.

0.6 ml - single-dose glass syringes (5) - blisters (1) - cardboard packs.

The solution for IV and IV administration is clear, colorless or with a yellowish tinge.

0.72 ml

dalteparin sodium 18,000 IU (anti-Xa)

Auxiliary substances: water d / and.

0.72 ml - single-dose glass syringes (5) - blisters (1) - cardboard packs.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2010.

PHARMACHOLOGIC EFFECT

Anticoagulant direct action.
It is a low molecular weight heparin isolated during the controlled depolymerization (with nitrous acid) of sodium heparin from the mucous membrane of the small intestine of the pig and subjected to additional purification by ion exchange chromatography. It consists of sulfated polysaccharide chains having an average molecular weight of 5,000 daltons; with 90% having a molecular weight of 2,000 to 9,000 daltons; the degree of sulfation is from 2 to 2.5 per disaccharide.
It binds plasma antithrombin, as a result of which it inhibits the activity of factor Xa and thrombin.
The anticoagulant effect of sodium dalteparin is due primarily to the inhibition of factor Xa; for blood coagulation time affects slightly. Compared to heparin, it has a weak effect on platelet adhesion and thus has less effect on primary hemostasis.
PHARMACOKINETICS

The pharmacokinetic parameters of sodium dalteparin do not change depending on the administered dose of the drug.

Suction

After the sc administration, the bioavailability of sodium dalteparin is about 90%.

Excretion

T 1/2 after intravenous administration is 2 hours, after SC administration - 3-5 hours. Dalteparin sodium is excreted mainly by the kidneys, however, the biological activity of fragments excreted in the urine is insufficiently studied.
In urine, less than 5% of anti-Xa activity is determined. The clearance of the anti-Xa activity of dalteparin from plasma after a single IV bolus administration at a dose of 30 and 120 IU (anti-Xa) / kg averages 24.6 ± 5.4 and 15.6 ± 2.4 ml / h / kg, respectively, and T 1/2 - 1.47 ± 0.3 and 2.5 ± 0.3 h.
Pharmacokinetics in special clinical cases

In patients with uremia, T 1/2 increases.

In patients with chronic renal insufficiency treated with hemodialysis, after a single intravenous administration of dalteparin sodium at a dose of 5000 ME T 1/2 , determined by anti-Xa activity, was 5.7 ± 2 hours and was significantly higher than in healthy volunteers.
Accordingly, in such patients, one can expect a more pronounced cumulation of the drug.
INDICATIONS

- Acute thrombosis of deep veins;

- pulmonary embolism;

- prophylaxis of blood coagulation in the extracorporeal circulation system during hemodialysis or hemofiltration in patients with acute or chronic renal insufficiency;

- prophylaxis of thrombus formation during surgical interventions;

- prophylaxis of thromboembolic complications in patients with a therapeutic disease in the acute phase and limited mobility (including under conditions requiring bed rest);

- unstable angina and myocardial infarction (without a pathological 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 oncological diseases.

DOSING MODE

Fragmin ® can not be administered in / m!

Treatment of acute deep vein thrombosis and pulmonary embolism

Fragmin ® is administered p / to 1-2 times / day.
In this case, you can immediately begin therapy with indirect anticoagulants (antagonists of vitamin K). Such combination therapy should be continued until the prothrombin index reaches the therapeutic level (usually no earlier than 5 days). Treatment of patients in outpatient settings can be carried out at doses recommended for inpatient therapy.
With the administration of 1 time / day, a dose of 200 IU / kg of body weight is given by sc.
Single dose should not exceed 18 000 IU. Monitoring anticoagulant activity of the drug can not be carried out.
With the introduction of 2 times / day, 100 IU / kg body weight is injected n / k.
Monitoring of anticoagulant activity of the drug can be avoided, but it should be taken into account that it may be required in the treatment of certain groups of patients. The recommended maximum concentration of the drug in the blood plasma should be 0.5-1 IU anti-Xa / ml.
Prevention of blood coagulation in the extracorporeal circulation system during hemodialysis or hemofiltration

Fragmin ® is administered iv.

Patients with chronic renal insufficiency or patients without risk of bleeding usually require a minor correction of the dosing regimen, so in most cases there is no need for frequent monitoring of the anti-Xa level.
When the recommended doses are administered during hemodialysis, an anti-Xa activity level of 0.5-1 IU / ml is usually achieved. If the duration of hemodialysis or hemofiltration is not more than 4 hours, the drug is administered intravenously intravenously with 30-40 IU / kg body weight, followed by iv infusion at a rate of 10-15 IU / kg / hr or once in a dose of 5000 IU. With the duration of hemodialysis or haemofiltration for more than 4 hours , intravenous administration of the drug in a dose of 30-40 IU / kg is carried out, followed by iv infusion at a rate of 10-15 IU / kg / h.
When using Fragmin in patients with acute renal failure or in patients with a high risk of bleeding, the drug is injected intravenously at a rate of 5-10 IU / kg, followed by IV infusion at a rate of 4-5 IU / kg / h.
In carrying out emergency hemodialysis (for acute renal failure), more careful monitoring of the level of anti-Xa activity is required, since the range of therapeutic doses for such patients is much narrower than for patients who are in chronic hemodialysis. The recommended maximum level of anti-Xa activity in plasma should be within 0.2-0.4 IU / ml.
Prevention of thrombosis during surgical interventions

Fragmin ® is administered sc.
Monitoring of anticoagulant activity, as a rule, is not required. When the drug is used in recommended doses, C max in plasma is 0.1 to 0.4 IU anti-Xa / ml.
When performing surgery in general surgical practice in patients with a risk of developing thromboembolic complications, the drug is administered SC at a dose of 2500 IU for 2 hours before the operation, then after surgery at 2500 IU / day (every morning) for the entire period until the patient is on bed rest (usually 5-7 days).

Patients with additional risk factors for thromboembolic complications (including patients with malignant tumors) Fragmin ® should be used throughout the period the patient is on bed rest (usually 5-7 days or more).
At the beginning of therapy the day before the surgery, Fragmin ® is administered SC at a dose of 5000 IU on the eve of surgery, then after an operation of 5000 IU every evening. At the beginning of therapy on the day of the operation, enter n / k 2500 ME for 2 hours before the operation and 2500 IU after 8-12 hours, but not earlier than 4 hours after the end of the operation; then the next day every morning for 5000 IU.
When performing orthopedic operations (for example, with hip replacement), Fragmin ® should be injected for up to 5 weeks after surgery by selecting one of the alternative dosing regimens.
At the beginning of therapy, the drug is administered at a dose of 5000 IU in the evening, on the eve of the operation, then 5000 IU every evening after the operation. At the beginning of therapy on the day of the operation, Fragmin ® is administered SC at a dose of 2500 IU for 2 hours before the operation and 2500 IU after 8-12 hours, but not earlier than 4 hours after the end of the operation; then the next day every morning - 5000 IU each.
At the beginning of therapy after surgery, the drug is administered SC in a dose of 2500 IU through 4-8 hours after the operation, but not earlier than 4 hours after the end of the operation;
then from the next day, sc, 5000 IU / day.
Prevention of thromboembolic complications in patients with a therapeutic disease in the acute phase and limited mobility (including under conditions requiring bed rest)

Fragmin ® should be injected s / c 5000 IU 1 time / day, usually for 12-14 days or longer (in patients with continuing mobility restriction).
Monitoring of anticoagulant activity, as a rule, is not required.
Unstable angina or myocardial infarction without an abnormal Q wave on the ECG

Monitoring of anticoagulant activity, as a rule, is not required, but it should be borne in mind that it may be required in the treatment of special groups of patients.
The recommended C max drug in plasma should be 0.5-1 IU anti-Xa / ml (simultaneously it is advisable to conduct therapy with acetylsalicylic acid at a dose of 75 to 325 mg / day). Fragmin ® is administered sc, 120 IU / kg body weight every 12 hours. The maximum dose should not exceed 10,000 IU / 12 hours. Therapy should be continued until the patient's clinical condition becomes stable (usually at least 6 days) or longer (at the doctor's discretion). Then it is recommended to switch to a long-term therapy with Fragmin in a constant dose right up to revascularization (percutaneous interventions or aortocoronary bypass surgery). The total duration of therapy should not exceed 45 days.
The dose of Fragmin is selected taking into account the sex and body weight of the patient.
Women with a body weight of <80 kg and men with a body weight <70 kg should be given a dose of 5000 meU every 12 hours. Women with a body weight? 80 kg and men with a body weight? 70 kg should be administered at 7500 IU SC every 12 hours.
Long-term treatment to prevent recurrence of venous thrombosis in patients with cancer

1 month - appoint sc in a dose of 200 IU / kg of body weight 1 time / day.
The maximum daily dose is 18 000 ME.
2-6 months - appoint SC at a dose of about 150 IU / kg body weight 1 time / day, using syringes with a fixed dose in accordance with Table 1.

Table 1. Determination of the dose of Fragmin ® in relation to body weight for the treatment period of 2-6 months.

Body weight (kg) Fragmin dose (ME)

?
56 7,500
57-68 10 000

69-82 12 500

83-98 15 000

?
99 18,000
When thrombocytopenia developed against the background of chemotherapy with a platelet count <50 000 / μL, the use of Fragmin
should be suspended until the platelet count increased to more than 50 000 / μL. For a platelet count of 50,000 / μL to 100,000 / μL, the dose of the drug should be reduced by 17-33% relative to the initial dose, depending on the patient's body weight in accordance with Table 2. When the platelet count is restored to the level of? 100 000 / mkl drug should be given in a full dose.
Table 2. Decrease in the dose of Fragmin ® with thrombocytopenia 50 000 / μL-100 000 / μL

Body weight (kg) Planned dose of Fragmin (ME) Reduced dose of Fragmin (ME) Dose reduction (%)

?
56 7,500 5,000 33
57-68 10 000 7 500 25

69-82 12 500 10 000 20

83-98 15 000 12 500 17

?
99 18 000 15 000 17
For renal insufficiency of a severe degree with a level of creatinine more than 3 times higher than IGN, the dose of Fragmin should be adjusted in such a way as to maintain the therapeutic level of anti-Xa 1 IU / ml (range 0.5-1.5 IU / ml), determined during 4- 6 hours after the administration of the drug.
If the anti-Xa level is below or above the therapeutic range, the dose of Fragmin should be increased or decreased, respectively, and the anti-Xa measurement should be repeated after the administration of 3-4 new doses. Correction of the dose should be carried out until the therapeutic level of anti-Xa is reached.
SIDE EFFECT

Adverse events are observed on average in 1% of patients.

From the hemopoietic system and the coagulating system of blood: bleeding, hematoma at the injection site, reversible non-immune thrombocytopenia, bleeding;
in some cases - immune thrombocytopenia (with or without thrombotic complications); development of spinal or epidural hematoma, peritoneal and intracranial hemorrhage, some of which are fatal.
From the side of the digestive system: a transient increase in the activity of liver transaminases (AST, ALT).

Local reactions: soreness at the injection site;
in some cases - necrosis of the skin.
Other: allergic reactions, in some cases - anaphylactic reactions.

CONTRAINDICATIONS

- immune thrombocytopenia (caused by heparin) in the anamnesis or suspicion of it;

- bleeding (clinically significant, for example, from the gastrointestinal tract against a stomach ulcer and / or duodenal ulcer, intracranial bleeding);

- severe disorders of the blood coagulation system;

- septic endocarditis;

- recent trauma or surgical interventions on the central nervous system, eyesight, hearing;

- hypersensitivity to the components of the drug;

- hypersensitivity to other low molecular weight heparins and / or to heparin.

Due to the increased risk of bleeding Fragmin ® in high doses (used, for example, for the treatment of acute deep vein thrombosis, pulmonary embolism, unstable angina and myocardial infarction without abnormal Q wave on the ECG) can not be administered to patients who are scheduled to undergo spinal or epidural anesthesia , or other procedures accompanied by lumbar puncture.

With caution , especially in patients in the early postoperative period, Fragmin ® should be given in high doses (for example, for acute deep vein thrombosis, pulmonary embolism, unstable angina and myocardial infarction without Q-wave on the ECG);
with caution should be appointed Fragmin ® to patients with an increased risk of bleeding, incl. patients with thrombocytopenia, impaired platelet function, severe hepatic or renal insufficiency, uncontrolled arterial hypertension, hypertensive or diabetic retinopathy.
PREGNANCY AND LACTATION

When used in pregnant women, there was no adverse effect on the course of pregnancy, as well as on the health of the fetus and the newborn.
When applying Fragmine in pregnancy, the risk of adverse effects on the fetus is assessed as low. However, since the possibility of adverse effects can not be completely ruled out, Fragmin ® can be prescribed only on strict indications, when the prospective benefit to the mother exceeds the potential risk.
If it is necessary to use Fragmin during pregnancy, it is necessary to monitor the anticoagulant activity of the drug.

In experimental studies, there was no teratogenic or fetotoxic effect of the drug.

It is not established whether sodium dalteparin is excreted in breast milk.

APPLICATION FOR FUNCTIONS OF THE LIVER

Patients with chronic renal insufficiency or patients with no risk of bleeding usually require a minor correction of the dosing regimen, so there is no need for frequent monitoring of the anti-Xa level.
When the recommended doses are administered during hemodialysis, an anti-Xa activity level of 0.5-1 IU / ml is usually achieved. If the duration of hemodialysis or hemofiltration is not more than 4 hours, the drug is administered intravenously intravenously with 30-40 IU / kg body weight, followed by iv infusion at a rate of 10-15 IU / kg / hr or once in a dose of 5000 IU. With the duration of hemodialysis or haemofiltration for more than 4 hours, intravenous administration of the drug in a dose of 30-40 IU / kg is carried out, followed by IV infusion at a rate of 10-15 IU / kg / h.
When using Fragmin in patients with acute renal failure or in patients with a high risk of bleeding, the drug is injected intravenously at a rate of 5-10 IU / kg, followed by IV infusion at a rate of 4-5 IU / kg / h.
In carrying out emergency hemodialysis (for acute renal failure), more careful monitoring of the level of anti-Xa activity is required, since the range of therapeutic doses for such patients is much narrower than for patients who are in chronic hemodialysis. The level of anti-Xa activity should be within 0.2-0.4 IU / ml.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Caution should be given to Fragmin ® in patients with severe hepatic insufficiency.

APPLICATION FOR CHILDREN

There is only limited information about the safety and effectiveness of the use of Fragmin in pediatric practice.
When using Fragmin in children, it is necessary to control the level of anti-Xa activity.
SPECIAL INSTRUCTIONS

The drug should not be administered in a / m!
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 heparin for the prevention of thromboembolic complications are at increased risk of spinal or epidural hematoma, which in turn which can result in 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 (NSAIDs, inhibitors of platelet function, other anticoagulants). The risk also increases with injuries and repeated epidural or lumbar puncture.In such cases, patients should be kept under constant surveillance for the early detection of abnormal neurological symptoms. When the neurological pathology is shown holding an urgent decompression of the spinal cord.
No clinical data on the application of Fragmin at a pulmonary embolism in patients with impaired circulation, hypotension or shock.
With the rapid development of the therapy Fragmin thrombocytopenia or thrombocytopenia with platelet counts less than 100,000 / mm is recommended to test for in vitro anti-platelet antibodies in the presence of heparin or low molecular weight heparins. If the results of such in vitro tests are positive or equivocal or testing generally is not held, the Fragmin ® should be discontinued.
The Fragmin monitoring of anticoagulation activity, as a rule, there is no need. However, it should be carried out in the application of Fragmin in children, patients with a body weight lower than normal or obese, pregnant women, as well as 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 h after s / c injection).
To determine the activity of anti-Xa method of choice are laboratory tests, which use a chromogenic substrate. Tests should not be used to determine the APTT and thrombin time as these tests are relatively insensitive to sodium dalteparin activity. Increasing doses of Fragmin to increase APTT may cause bleeding.
AUs Fragmin, unfractionated heparin and other low molecular weight heparins are not equal, however replacing one other drug is required to produce a correction mode.
When using a multidose vial unused solution to be destroyed within 14 days after the first puncturing needle tube.
Use in Pediatrics

There are only limited data on the safety and efficacy of Fragmin in pediatric practice. In the application of Fragmin in children is necessary to control the level of anti-Xa activity.
OVERDOSE

Symptoms: when an excessive dose may develop bleeding complications. In overdose in most cases possible bleeding of the skin and mucous membranes, gastrointestinal tract and urogenital tract. Lower blood pressure, decrease in hematocrit and other symptoms may be indicative of occult bleeding.
Treatment: in case of bleeding the use of Fragmin should be suspended to assess the severity of bleeding and the 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) dalteparin sodium (and, although indicated complete neutralization induced increase in clotting time, between 25% and 50% anti-Xa activity dalteparin sodium nevertheless persists.
DRUG INTERACTION

While the use of drugs affecting hemostasis, such as thrombolytic agents (alteplase, streptokinase, urokinase), oral anticoagulants, vitamin K antagonists, NSAIDs (including acetylsalicylic acid, indomethacin), as well as inhibitors of platelet function, anticoagulant effect Fragmin may be exacerbated (increased risk of bleeding).
Pharmaceutical interaction

Fragmin ® compatible with isotonic sodium chloride solution (9 mg / ml), isotonic dextrose (glucose) (50 mg / ml).
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

A preparation in the vials should be stored at a temperature not higher than 30 ° C, in syringes - at a temperature not higher than 25 ° C.
Shelf life - 3 years.
The drug should be stored out of the reach of children.

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