Fragmin solution d/in 2500 IU (anti-Xa)/0.2 ml x10 144106

Pharmacological properties of the drug Fragmin

Pharmacodynamics. The antithrombotic effect of dalteparin is associated with its ability to enhance the inhibition of factor Xa and thrombin. In general, dalteparin enhances the inhibition of factor Xa rather than prolonging the time of thrombus formation in the blood plasma. Dalteparin has almost no effect on the primary link of hemostasis since its effect on the function and adhesive properties of platelets is insignificant compared to heparin. Pharmacokinetics. Bioavailability, measured by antifactor Xa activity, was 87±6% in healthy patients. Increasing the drug dose from 2500 to 10,000 IU caused a proportional increase in the AUC for antifactor Xa by almost 1/3. The volume of distribution of anti-factor Xa activity of dalteparin was 40–60 ml/kg. After intravenous administration of 40 and 60 IU/kg, the mean terminal half-life was 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. After subcutaneous administration, a significant increase in the terminal half-life (3–5 hours) is observed, which may be due to slower absorption. Dalteparin is primarily excreted by the kidneys, but the biological activity of the fragments of the molecule that are excreted by the kidneys has not been well studied. ≤5% anti-Xa activity is detected in urine. In healthy volunteers, after a single intravenous bolus administration of 30 and 120 antifactor Xa IU/kg, the average plasma clearance of antifactor Xa activity was 24.6±5.4 and 15.6±0.3 hours. Hemodialysis. In patients with chronic renal failure who require hemodialysis, the average half-life of anti-factor Xa activity after a single intravenous dose of 5000 IU dalteparin was 5.7 ± 2.0 hours, which significantly exceeds the values obtained in healthy volunteers, since these patients may experience greater accumulation of the drug. Regardless of the route of administration, dose or duration of treatment, no data were obtained that indicated the organotoxicity of the drug. Also, no mutagenic effect was noted. Animal studies have not revealed embryotoxic, fetotoxic or teratogenic effects or adverse effects on fertility, copulation or peri- and postnatal development.

Indications for use of the drug Fragmin

acute deep vein thrombosis, pulmonary embolism;
prevention of blood coagulation in the extracorporeal circulatory system during long-term hemodialysis or hemofiltration in patients with acute renal failure or chronic renal failure;
prevention of thrombus formation during surgical interventions;
prevention of thrombus formation in patients requiring long-term immobilization;
unstable angina or non- ST (non- Q );
long-term treatment of symptomatic venous thromboembolism (proximal deep vein thrombosis and/or pulmonary embolism) in order to reduce the frequency of relapses of venous thromboembolism in patients with cancer.

Fragmin solution d/in 2500 IU (anti-Xa)/0.2 ml x10

Indications: acute deep vein thrombosis, pulmonary embolism,

- prevention of blood coagulation in the extracorporeal circulatory system during hemodialysis or hemofiltration in patients with acute or chronic renal failure,

- prevention of thrombus formation during surgical interventions,

— prevention of thromboembolic complications in patients with a therapeutic disease in the acute phase and limited mobility (including in conditions requiring bed rest),

- unstable angina and myocardial infarction (without pathological Q wave on the ECG),

- long-term treatment (up to 6 months) to prevent recurrence of venous thrombosis and pulmonary thromboembolism in patients with cancer.

ICD-10 codes ICD-10 code Indication I20.0 Unstable angina I21 Acute myocardial infarction I26 Pulmonary embolism I74 Embolism and thrombosis of arteries I82 Embolism and thrombosis of other veins

Dosage regimen Fragmin® cannot be administered intramuscularly!

Treatment of acute deep vein thrombosis and pulmonary embolism

Fragmin® is administered subcutaneously 1-2 times a day. In this case, you can immediately begin therapy with indirect anticoagulants (vitamin K antagonists). This combination therapy should be continued until the prothrombin index reaches a therapeutic level (usually no earlier than 5 days). Treatment of patients on an outpatient basis can be carried out in doses recommended for inpatient therapy.

When administered 1 time/day, a dose of 200 IU/kg body weight is administered subcutaneously. A single dose should not exceed 18,000 IU. Monitoring of the anticoagulant activity of the drug may not be carried out.

When administered 2 times/day, 100 IU/kg body weight is administered subcutaneously. Monitoring of the anticoagulant activity of the drug may not be necessary, but it should be borne in mind that this may be required when treating certain groups of patients. The recommended maximum concentration of the drug in 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 intravenously.

Patients with chronic renal failure or patients without a risk of bleeding usually require minor dosage adjustments, so in most cases there is no need for frequent monitoring of anti-Xa levels. When administered at recommended doses during hemodialysis, an anti-Xa activity level of 0.5-1 IU/ml is usually achieved. When hemodialysis or hemofiltration lasts no more than 4 hours, the drug is administered intravenously in a bolus at 30-40 IU/kg body weight, followed by intravenous drip administration at a rate of 10-15 IU/kg/h or a single bolus at a dose of 5000 IU. If hemodialysis or hemofiltration lasts more than 4 hours, intravenous jet administration of the drug is carried out at a dose of 30-40 IU/kg, followed by intravenous drip administration 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 administered intravenously at a rate of 5-10 IU/kg, followed by intravenous drip administration at a rate of 4-5 IU/kg/h. When performing 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 on chronic hemodialysis. The recommended maximum level of anti-Xa activity in plasma should be in the range of 0.2-0.4 IU/ml.

Prevention of thrombus formation during surgical interventions

Fragmin® is administered subcutaneously. Monitoring of anticoagulant activity is generally not required. When using the drug in recommended doses, Cmax in plasma ranges from 0.1 to 0.4 IU anti-Xa/ml.

When performing an operation in general surgical practice in patients at risk of developing thromboembolic complications, the drug is administered subcutaneously at a dose of 2500 IU 2 hours before surgery, then after surgery at 2500 IU/day (every morning) for the entire period while the patient is on bed rest (usually 5-7 days).

For patients with additional risk factors for the development of thromboembolic complications (including patients with malignant tumors), Fragmin® should be used for the entire period while the patient is on bed rest (usually 5-7 days or more). In this case, when starting therapy the day before surgery, Fragmin® is administered subcutaneously at a dose of 5000 IU in the evening before surgery, then after surgery, 5000 IU every evening. When starting therapy on the day of surgery, 2500 IU is administered subcutaneously 2 hours before surgery and 2500 IU 8-12 hours later, but not earlier than 4 hours after the end of the operation, then from the next day 5000 IU every morning.

When performing orthopedic operations (for example, hip replacement), Fragmin® should be administered for up to 5 weeks after surgery, choosing one of the alternative dosing regimens. When starting therapy, the drug is administered at a dose of 5000 IU subcutaneously in the evening on the eve of surgery, then 5000 IU every evening after surgery. When starting therapy on the day of surgery, Fragmin® is administered subcutaneously at a dose of 2500 IU 2 hours before surgery and 2500 IU 8-12 hours later, but not earlier than 4 hours after the end of the operation, then from the next day every morning - 5000 IU.

When starting therapy after surgery, the drug is administered subcutaneously at a dose of 2500 IU 4-8 hours after surgery, but not earlier than 4 hours after the end of the operation, then from the next day subcutaneously at a dose of 5000 IU/day.

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

Fragmin® should be administered subcutaneously at 5000 IU 1 time / day, usually for 12-14 days or longer (in patients with ongoing limitation of mobility). Monitoring of anticoagulant activity is generally not required.

Unstable angina or myocardial infarction without a pathological Q wave on the ECG

Monitoring of anticoagulant activity is generally not required, but it should be kept in mind that it may be required in the treatment of special groups of patients. The recommended Cmax of the drug in plasma should be 0.5-1 IU anti-Xa/ml (at the same time, it is advisable to carry out therapy with acetylsalicylic acid in a dose of 75 to 325 mg/day). Fragmin® is administered subcutaneously at 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 discretion of the doctor). Then it is recommended to switch to long-term therapy with Fragmin at a constant dose until revascularization (percutaneous interventions or coronary artery bypass grafting). The total duration of therapy should not exceed 45 days.

The dose of Fragmin is selected taking into account the gender and body weight of the patient. Women with weight Long-term treatment to prevent recurrence of venous thrombosis in patients with cancer

1 month - prescribed subcutaneously at a dose of 200 IU/kg body weight 1 time/day. The maximum daily dose is 18,000 IU.

2-6 months - prescribe subcutaneously 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® depending on body weight for a 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

For thrombocytopenia that developed during chemotherapy with platelet count Table 2. Reducing the dose of Fragmin® for thrombocytopenia 50,000/μl-100,000/μl

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

In severe renal failure with a creatinine level more than 3 times the ULN, the dose of Fragmin should be adjusted to maintain a therapeutic anti-Xa level of 1 IU/ml (range 0.5-1.5 IU/ml), determined over 4- 6 hours after drug administration. If the anti-Xa level is below or above the therapeutic range, the dose of Fragmin should be increased or decreased accordingly, and the anti-Xa measurement should be repeated after administration of 3-4 new doses. Dose adjustments should be made until a therapeutic level of anti-Xa is achieved.

Side effects Side effects occur in an average of 1% of patients.

From the hematopoietic system and blood coagulation system: 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 bleeding, some of which with fatal outcome.

From the digestive system: transient increase in the activity of liver transaminases (AST, ALT).

Local reactions: pain at the injection site, in some cases - skin necrosis.

Other: allergic reactions, in some cases - anaphylactic reactions.

Contraindications to use: a history of immune thrombocytopenia (caused by heparin) or suspicion of it,

- bleeding (clinically significant, for example, from the gastrointestinal tract against the background of gastric and/or duodenal ulcers, intracranial bleeding),

- severe disorders of the blood coagulation system,

- septic endocarditis,

- recent injuries or surgical interventions on the central nervous system, organs of vision, hearing,

- hypersensitivity to the components of the drug,

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

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

Fragmin® should be prescribed with caution, especially to patients in the early postoperative period, in high doses (for example, for the treatment of acute deep vein thrombosis, pulmonary embolism, unstable angina and myocardial infarction without a Q wave on the ECG), Fragmin® should be prescribed with caution to patients with an increased risk of bleeding, incl. patients with thrombocytopenia, platelet dysfunction, severe liver or kidney failure, uncontrolled arterial hypertension, hypertensive or diabetic retinopathy.

Use during pregnancy and breastfeeding When used in pregnant women, no adverse effects on the course of pregnancy, as well as on the health of the fetus and newborn were identified. When using Fragmin during pregnancy, the risk of adverse effects on the fetus is assessed as low. However, since the possibility of adverse effects cannot be completely excluded, Fragmin® can be prescribed only for strict indications when the expected benefit to the mother outweighs the potential risk.

If it is necessary to use Fragmin during pregnancy, it is necessary to monitor the anticoagulant activity of the drug.

Experimental studies did not reveal any teratogenic or fetotoxic effects of the drug.

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

Use for liver dysfunction Fragmin should be prescribed with caution to patients with severe liver failure. Use for impaired renal function Patients with chronic renal failure or patients without a risk of bleeding usually require minor adjustments in the dosage regimen, so there is no need for frequent monitoring of anti-Xa levels. When administered at recommended doses during hemodialysis, an anti-Xa activity level of 0.5-1 IU/ml is usually achieved. When hemodialysis or hemofiltration lasts no more than 4 hours, the drug is administered intravenously in a bolus at 30-40 IU/kg body weight, followed by intravenous drip administration at a rate of 10-15 IU/kg/h or a single bolus at a dose of 5000 IU. If hemodialysis or hemofiltration lasts more than 4 hours, intravenous jet administration of the drug is carried out at a dose of 30-40 IU/kg, followed by intravenous drip administration 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 administered intravenously at a rate of 5-10 IU/kg, followed by intravenous drip administration at a rate of 4-5 IU/kg/h. When performing 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 on chronic hemodialysis. The level of anti-Xa activity should be in the range of 0.2-0.4 IU/ml.

Use in children There is only limited information about the safety and effectiveness of Fragmin in pediatric practice. When using Fragmin in children, it is necessary to monitor the level of anti-Xa activity. Special instructions The drug must not be administered intramuscularly!

When receiving neuraxial anesthesia (epidural/spinal anesthesia) or performing a lumbar puncture in patients who are receiving anticoagulant therapy or who are planned to undergo anticoagulant therapy using low molecular weight heparins to prevent thromboembolic complications, there is an increased risk of developing spinal or epidural hematoma, which the queue can lead to long-term or permanent paralysis. The risk of such complications increases when using permanent epidural catheters for the administration of analgesics or while using drugs that affect hemostasis (NSAIDs, platelet function inhibitors, other anticoagulants). The risk also increases with trauma and repeated epidural or lumbar punctures. In such cases, patients should be under constant observation for timely detection of pathological neurological symptoms. If neurological pathology occurs, immediate decompression of the spinal cord is indicated.

There are no clinical data on the use of Fragmin for pulmonary embolism in patients with circulatory disorders, arterial hypotension or shock.

If thrombocytopenia develops rapidly during Fragmin therapy or with thrombocytopenia with a platelet count of less than 100,000/μl, it is recommended to conduct an in vitro test for antiplatelet antibodies in the presence of heparin or low molecular weight heparins. If the results of such an in vitro test are positive or equivocal, or if no testing has been carried out at all, then Fragmin® should be discontinued.

Monitoring the anticoagulant activity of Fragmin is usually not necessary. However, it should be carried out when using Fragmin in children, patients with underweight or obesity, pregnant women, and also with an increased risk of bleeding or recurrent thrombosis.

Blood samples for analysis of Fragmin activity should be taken during the period when the maximum concentration of the drug in the blood plasma is reached (3-4 hours after subcutaneous injection).

To determine anti-Xa activity, the method of choice is laboratory tests that use a chromogenic substrate. APTT and thrombin time tests should not be used because these tests are relatively insensitive to the activity of dalteparin sodium. Increasing the dose of Fragmin in order to increase the aPTT may lead to bleeding.

The units of action of Fragmin, unfractionated heparin and other low molecular weight heparins are not equivalent, therefore, when replacing one drug with another, it is necessary to adjust the dosage regimen.

When using multi-dose vials, unused solution must be destroyed 14 days after the first piercing of the stopper with a needle.

Use in pediatrics

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

Overdose Symptoms: with an excessive dose, hemorrhagic complications may develop. In case of overdose, in most cases, bleeding of the skin and mucous membrane, gastrointestinal tract and urogenital tract is possible. A decrease in blood pressure, a decrease in hematocrit and other symptoms may indicate hidden 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 of Fragmin can be eliminated by the administration of protamine sulfate, which is an emergency treatment. 1 mg of protamine sulfate partially neutralizes the effect of 100 IU (anti-Xa) dalteparin sodium (and, although there is complete neutralization of the induced increase in clotting time, 25% to 50% of the anti-Xa activity of dalteparin sodium is still retained.

Conditions for dispensing from pharmacies The drug is dispensed with a prescription.

Conditions and periods of storage The drug in ampoules should be stored at a temperature not exceeding 30°C, in syringes - at a temperature not exceeding 25°C. Shelf life: 3 years.

The drug should be stored out of the reach of children.

Use of the drug Fragmin

Dalteparin should not be prescribed IM! Compatible with solutions administered intravenously. Dalteparin is compatible with isotonic sodium chloride solution (9 mg/ml) or isotonic glucose solution for infusion (50 mg/ml) in glass or plastic bottles. Acute deep vein thrombosis Fragmin is administered subcutaneously 1 or 2 times a day. At the same time, concomitant therapy with indirect oral anticoagulants (vitamin K antagonists) can be carried out. Combination therapy is continued until the required changes in the prothrombin index are achieved (usually for at least 5 days). The dosage of the drug does not change during outpatient or inpatient treatment. Administration 1 time per day. When administered once a day, Fragmin is prescribed subcutaneously at a dose of 200 IU/kg. The dose for a single administration should not exceed 18,000 IU. Monitoring of the anticoagulant activity of the drug may not be carried out. Administration 2 times a day. When administered 2 times a day, Fragmin is prescribed subcutaneously at 100 IU/kg for each administration. In general, monitoring of the anticoagulant activity of the drug may not be necessary (certain groups of patients are an exception). If necessary, perform a functional analysis of anti-Xa activity; Blood samples are taken for analysis 3–4 hours after drug administration, when the maximum level of anti-Xa activity in the blood serum is reached. The recommended level of anti-Xa activity in blood serum should be in the range of 0.5–1 anti-Xa/ml. Prevention of blood coagulation in the extracorporeal circulatory system during hemodialysis and hemofiltration When preventing blood coagulation in the extracorporeal circulatory system, Fragmin is administered intravenously, choosing the appropriate dosage regimen. Patients with chronic renal failure or patients without risk factors for bleeding. Such patients are usually given only a few doses of Fragmin, so there is no need to monitor anti-Xa levels in most patients. The use of the drug in recommended doses ensures the level of anti-Xa during dialysis in the range of 0.5–1 IU anti-Xa/ml. With a duration of hemodialysis or hemofiltration of a maximum of 4 hours. The drug can be administered to adults at a dose of 30–40 IU/kg body weight as an IV bolus with further fractional administration of 10–15 IU/kg/h or as an IV bolus at a dose of 5000 IU . When the duration of hemodialysis or hemofiltration is 4 hours. For adults, the drug is administered intravenously as a bolus at a dose of 30–40 IU/kg body weight, then dropwise at a rate of 10–15 IU/kg/h. ARF or patients at high risk of bleeding. For acute renal failure in patients with a high risk of bleeding, the drug is administered intravenously as a bolus at a dose of 5–10 IU/kg, then intravenously at a rate of 4–5 IU/kg/h. The number of patients undergoing hemodialysis for acute indications is smaller than the number of patients undergoing hemodialysis for chronic indications and they should be closely monitored for anti-Xa levels. It is recommended to achieve a level of factor Xa suppression activity in blood plasma within the range of 0.2–0.4 IU/ml. Prevention of thromboembolic complications during surgical interventions The drug is administered subcutaneously. Monitoring of anticoagulant activity may not be necessary. If necessary, anti-Xa activity is assessed; blood samples are taken for analysis 3–4 hours after administration of the drug, when the maximum level of anti-Xa activity in the blood serum is reached. Use at the recommended dose typically produces a maximum level of anti-Xa activity in the blood plasma of 0.1–0.4 IU anti-Xa/ml. General surgery Use in cases of high risk of thromboembolism. Adult patients are administered subcutaneously at a dose of 2500 IU 1–2 hours before surgery and then 2500 IU subcutaneously every morning after surgery for the entire period while the patient is on bed rest (usually for 5–7 days or more). If there are additional risk factors for the development of thromboembolic complications (for example, in patients with malignant neoplasms). The drug should be administered for as long as the patient is on bed rest (usually 5–7 days or more). Start of use the day before surgery - administer 5000 IU subcutaneously in the evening before surgery, then 5000 IU every evening. Start of use on the day of surgery - adults are administered 2500 IU subcutaneously 1–2 hours before surgery and 2500 IU 8–12 hours later, but not earlier than 4 hours after the end of the operation. Starting from the next day after surgery, 5000 IU is prescribed subcutaneously every morning. Orthopedic surgeries (for example, joint replacement) The drug can be administered up to 5 weeks after surgery according to one of the following regimens. Beginning of therapy in the evening before surgery - adults are administered 5000 IU subcutaneously in the evening before the day of surgery, after surgery they are administered 5000 IU subcutaneously every evening. Start of therapy on the day of surgery - administer 2500 IU subcutaneously 2 hours before surgery and 2500 IU subcutaneously 8–12 hours later, but not earlier than 4 hours after surgery. Starting the next day after surgery, 5000 IU is administered subcutaneously every morning. Beginning of therapy after surgery - adults are administered 2500 IU subcutaneously 4–8 hours after surgery, but not earlier than 4 hours after its completion. Starting from the next day after surgery, 5000 IU is administered subcutaneously daily. Prevention of thromboembolic complications in patients with limited mobility Adults use 5000 IU Fragmin subcutaneously once a day for 12–14 days or more in patients with prolonged limited mobility. Monitoring the anticoagulant effect of the drug in most cases is not required. Unstable angina and myocardial infarction without elevation of the S-T interval Fragmin is administered subcutaneously at a dose of 120 IU/kg 2 times a day every 12 hours, not exceeding the dose of 10,000 IU/12 hours. In the absence of contraindications, concomitant therapy with acetylsalicylic acid in low doses is recommended doses (75–325 mg/day). Treatment should be continued for at least 6 days or more until the patient's condition is clinically stabilized (at the discretion of the physician). The use of Fragmin in recommended doses should be continued until myocardial revascularization measures are carried out. The total duration of use should not exceed 45 days. The dose of the drug is selected taking into account the gender and body weight of the patient:

women weighing ≤80 kg and men weighing ≤70 kg are prescribed subcutaneously at a dose of 5000 IU every 12 hours;
women weighing 80 kg and men weighing 70 kg are prescribed subcutaneously at a dose of 7500 IU every 12 hours.

In most cases, monitoring the anticoagulant effect of the drug is not required, with the exception of certain groups of patients. In the case of such control, studies should be carried out 3-4 hours after subcutaneous injection, when the maximum level of anti-Xa activity in the blood plasma is reached. It is advisable to achieve a level of anti-Xa activity in the range of 0.5–1 IU anti-Xa/ml. Treatment of symptomatic venous thromboembolism to reduce the incidence of venous thromboembolic complications in patients with cancer 1st month. For adults, Fragmin is prescribed at a dose of 200 IU/kg body weight subcutaneously once a day in the first 30 days of treatment. The total daily dose should not exceed 18,000 IU. 2–6 months. For adults, Fragmin is prescribed at a dose of about 150 IU/kg body weight subcutaneously once a day, using a fixed amount of the drug in one syringe according to the data in the table. Doses of the drug during the 2nd–6th month of treatment

Body weight, kg	Dose of Fragmin, IU
≤56	7500
57–68	10 000
69–82	12 500
83–98	15 000
≥99	18 000

Dose reduction for patients with chemotherapy-induced thrombocytopenia In cases of chemotherapy-induced thrombocytopenia with a platelet count ≤50,000/mm3, use of Fragmin should be interrupted until the platelet count rises to 50,000/mm3. At platelet levels of 50,000–100,000/mm3, the dose of Fragmin should be reduced by 17–33% of the initial dose depending on the patient's body weight, as indicated in the table below. If the platelet count increases to 100,000/mm3, you should switch to the maximum dose of Fragmin. Reducing the dose of Fragmin for thrombocytopenia within the range of 50,000–100,000/mm3

Body weight, kg	Usual dose of Fragmin, IU	Reduced dose of Fragmin, IU	Average dose reduction,%
≤56	7500	5000	33
57–68	10 000	7500	25
69–82	12 500	10 000	20
83–98	15 000	12 500	17
≥99	18 000	15 000	17

Kidney failure. In case of severe renal failure (creatinine level 3 times higher than normal), the dose of Fragmin should be adjusted to maintain a level of anti-Xa activity of about 1 IU/ml (range 0.5–1.5 IU/ml), which should be determined 4–6 hours after injection of the drug. If the level of anti-Xa activity is above or below the therapeutic limit, the dose of Fragmin should be changed according to the amount of the drug in one syringe and the level of anti-Xa activity should be determined after administering new 3-4 doses of the drug. This dose adjustment should be repeated until a therapeutic level of anti-Xa activity is achieved.

Fragmin solution for intravenous and subcutaneous administration 5000 IU 0.2 ml syringe 10 pcs. in Moscow

INSTRUCTIONS for use

APPROVED by the Federal Committee of the Ministry of Health of the Russian Federation on May 30, 2002, pr. No. 1.

Description.

Transparent, colorless or yellowish solution.

Compound.
Active ingredient:
dalteparin sodium 2500 IU (anti-Xa)/0.2 ml, 5000 IU (anti-Xa)/0.2 ml, 10000 IU (anti-Xa)/ml, 7500 IU (anti-Xa)/0 ,3 ml, 10000 IU (anti-Xa)/0.4 ml, 12500 IU (anti-Xa)/0.5 ml, 15000 IU (anti-Xa)/0.6 ml and 18000 IU (anti-Xa) /0.72 ml respectively.

Excipients:

water for injection, sodium chloride, (sodium hydroxide or hydrochloric acid qs - for a solution of 2500 IU (anti-Xa)/0.2 ml and 5000 IU (anti-Xa)/0.2 ml).

Characteristic.

Dalteparin sodium is a low molecular weight heparin isolated by controlled depolymerization (with nitrous acid) of sodium heparin from the mucosa of the small intestine of pigs and subjected to further purification using ion exchange chromatography. The drug consists of sulfated polysaccharide chains with an average molecular weight of 5000 daltons; while 90% have a molecular weight from 2000 to 9000 daltons; degree of sulfation - from 2 to 2.5 per disaccharide.

Pharmacological properties.

Pharmacodynamics.

Dalteparin sodium inhibits the activity of factor Xa and thrombin through plasma antithrombin. The anticoagulant effect of dalteparin sodium is primarily due to the inhibition of factor Xa; The drug has a slight effect on blood clotting time. Compared with heparin, dalteparin sodium has a weak effect on platelet adhesion and, thus, has less effect on primary hemostasis.

Pharmacokinetics.

T1/2 after intravenous administration of the drug - 2 hours, after subcutaneous administration - 3-5 hours. Bioavailability after subcutaneous administration is approximately 90%; pharmacokinetic parameters are independent of dose. In patients with uremia, T1/2 of the drug increases. Dalteparin sodium is excreted primarily through the kidneys.

Indications for use.

Treatment of acute deep vein thrombosis and pulmonary embolism.

Prevention of blood coagulation in the extracorporeal circulatory system during hemodialysis or hemofiltration in patients with acute or chronic renal failure.

Prevention of thrombus formation during surgical interventions.

Unstable angina and myocardial infarction (without Q wave on ECG).

Contraindications.

Hypersensitivity to dalteparin sodium or to other low molecular weight heparins and/or heparin.

Immune thrombocytopenia (history of heparin-induced or suspected presence).

Bleeding (clinically significant, for example, from the gastrointestinal tract against the background of gastric and/or duodenal ulcers, intracranial bleeding).

Severe disorders of the blood coagulation system.

Septic endocarditis.

Recent injuries or surgical interventions on the central nervous system, visual and/or hearing organs.

Due to the increased risk of bleeding, high doses of Fragmin (eg, for the treatment of acute deep vein thrombosis, pulmonary embolism, unstable angina, and non-Q-wave myocardial infarction on the ECG) should not be given to patients who are scheduled for spinal or epidural anesthesia, or other procedures accompanied by lumbar puncture.

Precautionary measures.

High doses of Fragmin (for example, for the treatment of acute deep vein thrombosis, pulmonary embolism, unstable angina and myocardial infarction without a Q-wave on the ECG) should be prescribed with extreme caution to patients in the early postoperative period. Caution should be exercised when prescribing Fragmin to patients with an increased risk of bleeding; This group includes patients with thrombocytopenia, platelet dysfunction, severe liver or kidney failure, uncontrolled hypertension, hypertensive or diabetic retinopathy.

Method of administration and dose.

Fragmin cannot be administered intramuscularly.

Treatment of acute deep vein thrombosis and pulmonary embolism

Fragmin is administered subcutaneously 1–2 times a day. In this case, you can immediately begin therapy with indirect anticoagulants (vitamin K antagonists). This combination therapy should be continued until the prothrombin index reaches a therapeutic level (usually this is noted no earlier than after 5 days). Treatment of patients on an outpatient basis can be carried out in the same doses that are recommended for treatment in a hospital setting.

Administration 1 time per day - a dose of 200 IU/kg body weight is administered subcutaneously. A single daily dose should not exceed 18,000 IU. Monitoring the anticoagulant activity of the drug

may not be carried out.

Administration 2 times a day - 100 IU/kg body weight subcutaneously 2 times a day. Monitoring of anticoagulant activity may not be necessary, but it should be borne in mind that it may be required when treating special groups of patients (see section "Special Instructions"). The recommended plasma Cmax should be 0.5–1 IU anti-Xa/ml.

Prevention of blood coagulation in the extracorporeal circulation system during hemodialysis or hemofiltration

Fragmin should be administered intravenously, choosing a dosage regimen from those given below.

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

These patients usually require minor dosage adjustments and therefore there is no need for frequent monitoring of anti-Xa levels in most patients. When administered at recommended doses during hemodialysis, plasma levels of 0.5–1 IU anti-Xa/ml are typically achieved.

When the duration of hemodialysis or hemofiltration is no more than 4 hours

— IV bolus at 30–40 IU/kg body weight, followed by IV drip administration at 10–15 IU/kg/h, or a single IV bolus at a dose of 5000 IU.

If the duration of hemodialysis or hemofiltration is more than 4 hours

- intravenous injection of 30–40 IU/kg body weight, followed by intravenous drip administration of 10–15 IU/kg/hour.

Patients with acute renal failure, or patients at high risk of bleeding

IV jet administration of 5–10 IU/kg body weight followed by IV drip administration of 4–5 IU/kg/hour. In patients undergoing hemodialysis for acute renal failure, the drug is characterized by a narrower therapeutic index than in patients on chronic hemodialysis (and therefore they require adequate monitoring of anti-Xa levels). The recommended maximum plasma level should be 0.2–0.4 IU anti-Xa/ml.

Prevention of thrombus formation during surgical interventions

Fragmin should be administered subcutaneously. Monitoring of anticoagulant activity is generally not required. When using the drug in recommended doses, maximum plasma concentrations range from 0.1 to 0.4 IU anti-Xa/ml.

When performing operations in general surgical practice

Patients at risk of developing thromboembolic complications

- SC 2500 IU 2 hours before surgery, then after surgery - SC 2500 IU / day (every morning) for the entire period while the patient is on bed rest (usually 5-7 days).

Patients with additional risk factors for thromboembolic complications (eg, patients with malignancies)

— Fragmin should be used for the entire period while the patient is on bed rest (usually 5–7 days or more).

1. When starting therapy the day before surgery: 5000 IU subcutaneously on the evening before surgery, then 5000 IU subcutaneously every evening after surgery.

2. When starting therapy on the day of surgery: 2500 IU subcutaneously 2 hours before surgery and 2500 IU subcutaneously 8–12 hours later, but not earlier than 4 hours after the end of the operation. Then, from the next day, 5000 IU is administered s.c. every morning.

When performing orthopedic operations (for example, during hip replacement operations).

Fragmin should be administered for up to 5 weeks after surgery using one of the dosing regimens listed below.

1. When starting therapy the evening before surgery: 5000 IU subcutaneously the evening before surgery, then 5000 IU subcutaneously every evening after surgery.

2. When starting therapy on the day of surgery: 2500 IU subcutaneously 2 hours before surgery and 2500 IU subcutaneously 8–12 hours later, but not earlier than 4 hours after the end of the operation. Then from the next day every morning - 5000 IU subcutaneously.

3. When starting therapy after surgery: 2500 IU subcutaneously 4–8 hours after surgery, but not earlier than 4 hours after the end of surgery. Then from the next day, 5000 IU subcutaneously per day.

Unstable angina and myocardial infarction (without Q-wave on ECG)

Monitoring of anticoagulant activity is generally not required, but it should be borne in mind that it may be required when treating special groups of patients (see section "Special Instructions"). The recommended Cmax in plasma should be 0.5–1 IU anti-Xa/ml (at the same time, it is advisable to carry out therapy with acetylsalicylic acid in a dose of 75 to 325 mg/day). Fragmin is administered subcutaneously at 120 IU/kg body weight every 12 hours. The maximum dose should not exceed 10,000 IU every 12 hours. Therapy should be continued until the patient’s clinical condition becomes stable (usually at least 6 days), or longer (at the discretion of the doctor). Then it is recommended to switch to long-term therapy with Fragmin at a constant dose until revascularization (percutaneous interventions or coronary artery bypass grafting). The total duration of therapy should not exceed 45 days. The dose of Fragmin is selected taking into account the gender and body weight of the patient:

- women weighing less than 80 kg and men weighing less than 70 kg should be administered 5000 IU subcutaneously every 12 hours;

- women weighing 80 kg or more and men weighing 70 kg or more should be administered 7500 IU subcutaneously every 12 hours.

Side effect.

The following side effects are observed (on average in 1% of patients): bleeding, hematoma at the injection site, reversible non-immune thrombocytopenia, pain at the injection site, allergic reactions, as well as a transient increase in the activity of “liver” transaminases (AST, ALT). Several cases of immune thrombocytopenia (with or without thrombotic complications), as well as cases of skin necrosis, anaphylactic reactions, and the development of spinal or epidural hematoma, have been reported.

Overdose.

The anticoagulant effect of Fragmin can be eliminated by the administration of protamine sulfate, which is an emergency treatment. 1 mg of protamine partially neutralizes the effect of 100 IU (anti-Xa) dalteparin sodium (and although there is complete neutralization of the induced increase in clotting time, 25 to 50% of the anti-Xa activity of dalteparin sodium is still retained).

Interaction with other drugs and other forms of interactions.

When used simultaneously with drugs that affect hemostasis, such as thrombolytic agents, other anticoagulants, NSAIDs, and platelet function inhibitors, the anticoagulant effect of Fragmin may be enhanced.

Weakening of the effect when used together with antihistamines, cardiac glycosides, tetracyclines, ascorbic acid.

Compatible with solutions for intravenous administration.

Fragmin is compatible with isotonic sodium chloride solution (9 mg/ml) and isotonic dextrose solution (50 mg/ml).

Special instructions.
Fragmin cannot be administered intramuscularly.
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is performed in patients who are receiving anticoagulant therapy, or who are planned to undergo anticoagulant therapy using low molecular weight heparins or heparinoids to prevent thromboembolic complications, there is an increased risk of developing epidural or spinal hematoma. which in turn can lead to long-term or permanent paralysis. The risk of such complications increases with the use of indwelling epidural catheters for the administration of analgesics or with the simultaneous use of drugs that affect hemostasis, such as NSAIDs, platelet function inhibitors and other anticoagulants. The risk also increases with trauma and with repeated epidural or lumbar punctures. In such cases, patients should be under constant observation for timely detection of pathological neurological symptoms. If a neurological pathology is detected, emergency intervention (spinal cord decompression) is indicated.

There are no clinical data on the use of Fragmin in patients with pulmonary embolism who also had circulatory disorders, arterial hypotension or shock.

Particular attention is required for patients who, when treated with Fragmin, experience rapid development of thrombocytopenia, or thrombocytopenia with a platelet count of less than 100,000/μl. In such cases, it is recommended to perform an in vitro test for antiplatelet antibodies in the presence of heparin or low molecular weight heparins. If the result of this in vitro test is positive or equivocal, or no testing has been performed at all, then treatment with Fragmin should be discontinued (see section "Contraindications").

Monitoring the anticoagulant activity of Fragmin is usually not necessary, however, it may be necessary when treating special groups of patients: children, patients with underweight or obesity, pregnant women, and patients with an increased risk of bleeding or recurrent thrombosis.

Blood samples for analysis of Fragmin activity should be taken during the period when Cmax in plasma is reached (3-4 hours after subcutaneous injection).

To determine anti-Xa activity, laboratory tests that use a chromogenic substrate are recognized as the method of choice. Activated partial thromboplastin time (aPTT) and thrombin time tests should not be used in this case because these tests are relatively insensitive to the activity of dalteparin sodium. Increasing the dose of Fragmin in order to increase the aPTT may lead to bleeding (see section "Overdose").

The units of action of Fragmin, unfractionated heparin and other low molecular weight heparins are not equivalent, therefore, when replacing one drug with another, a dose adjustment is required.

When using multi-dose vials, unused solution must be destroyed 14 days after the first piercing of the stopper with a needle.

Application in pediatric practice.

There is only limited information about the safety and effectiveness of Fragmin in pediatric practice. When using Fragmin in children, it is necessary to monitor the level of anti-Xa (see section “Method of administration and dosage”).

Pregnancy and breastfeeding.

In the experiment, Fragmin does not have a teratogenic or fetotoxic effect. When used in pregnant women, no adverse effects on the course of pregnancy were detected. as well as the health of the fetus and newborn. When using Fragmin during pregnancy, the risk of adverse effects on the fetus is assessed as low. However, since the possibility of adverse effects cannot be completely excluded, Fragmin during pregnancy can be prescribed only if there are clear indications when the expected benefit outweighs the possible risk. It has not been established whether Fragmin is excreted into breast milk.

Release form.

Solution for injection 10,000 ME (anti-Xa)/ml, 10 ampoules of 1 ml with instructions for use in a cardboard box.

Solution for injection 2500 IU (anti-Xa)/0.2 ml, 10 disposable syringes of 0.2 ml each with instructions for use in a cardboard box.

Solution for injection 5000 ME (anti-Xa)/0.2 ml, 10 disposable syringes of 0.2 ml each with instructions for use in a cardboard box.

Solution for injection 7500 ME (anti-Xa)/0.3 ml, 10 disposable syringes of 0.3 ml with instructions for use in a cardboard box.

Injection solution 10,000 ME (anti-Xa)/0.4 ml, 5 disposable syringes of 0.4 ml each with instructions for use in a cardboard box.

Solution for injection 12500 ME (anti-Xa)/0.5 ml, 5 disposable syringes of 0.5 ml with instructions for use in a cardboard box.

Solution for injection 15000 ME (anti-Xa)/0.6 ml, 5 disposable syringes of 0.6 ml with instructions for use in a cardboard box.

Solution for injection 18000 ME (anti-Xa)/0.72 ml, 5 disposable syringes of 0.72 ml with instructions for use in a cardboard box.

Storage conditions.

Store out of the reach of children, at a temperature not exceeding 30 °C.

Best before date.

3 years.

Conditions for dispensing from pharmacies.

By doctor's prescription.

Manufacturer.

Disposable syringes: Pharmacia N.V./S.A., Belgium, manufactured by Vetter Pharma-Fertigung GmbH, Germany.

Ampoules: Pharmacy and Upjohn N.V./S.A., Belgium.

Contraindications to the use of the drug Fragmin

reliable or probable history data on the presence of immune heparin-induced thrombocytopenia;
active clinically significant bleeding (peptic ulcer of the stomach or duodenum, clinical manifestations of active ulcer bleeding or cerebral hemorrhage);
severe blood clotting disorders;
septic endocarditis;
injuries to the central nervous system, organs of vision, hearing, as well as surgical interventions on these organs;
hypersensitivity to dalteparin and other heparins. In addition, high doses of Fragmin (used in the treatment of acute deep vein thrombosis, pulmonary thromboembolism or unstable angina) should not be used in patients who have received spinal or epidural anesthesia or spinal puncture, as there is a high risk of bleeding.

Side effects of the drug Fragmin

During clinical studies, the following side effects occurred with a frequency of 1%:

from the blood and lymphatic systems - reversible thrombocytopenia of non-immune origin (type I);
hepatobiliary disorders - transient increase in the activity of liver transaminases (ALAT, AST);
general disorders and changes at the injection site - bleeding, hematoma formation at the injection site, allergic reactions, pain at the injection site.

The following violations have been reported post-marketing:

on the part of the blood and lymphatic system - the appearance of immune heparin-induced thrombocytopenia (type II) in combination with or without thrombotic complications;
from the skin - skin necrosis, alopecia;
from the immune system - anaphylactic reactions;
injuries, poisoning and complications of procedures - spinal or epidural hematomas, retroperitoneal and intracranial hemorrhages, which can sometimes be fatal.

Special instructions for the use of the drug Fragmin

Epidural or spinal anesthesia. When conducting anticoagulant therapy to prevent thromboembolic complications (anticoagulants of the group of low molecular weight heparins or heparinoids) in patients who have undergone neuraxial anesthesia (epidural or spinal) or spinal puncture, there is a risk of developing an epidural or spinal hematoma, which can cause prolonged or irreversible paralysis. The risk of developing this complication increases when using an indwelling epidural catheter for prolonged anesthesia or while using drugs that affect hemostasis (NSAIDs, platelet aggregation inhibitors or other anticoagulants). The risk also increases with traumatic or repeated epidural or spinal puncture. Such patients should be monitored frequently for neurological complications. If neurological symptoms are detected, therapy with spinal cord decompression should be immediately performed. Risk of bleeding. The drug should be used with caution in patients with an increased risk of bleeding, namely in patients with thrombocytopenia, impaired platelet function, severe renal or hepatic impairment, uncontrolled hypertension (arterial hypertension) and in patients with hypertensive or diabetic retinopathy. Caution should also be exercised when treating Fragmin in high doses (necessary for the treatment of deep vein thrombosis, pulmonary embolism and unstable angina or myocardial infarction without ST ) in patients in the early postoperative period. Thrombocytopenia. Particular attention is required if thrombocytopenia develops rapidly or if there is a significant decrease in platelet levels (≤100,000/mm3) during treatment with Fragmin. In such cases, an in vitro to detect antiplatelet antibodies in the presence of heparin or low molecular weight heparin. If the results of such a test are positive or equivocal, or the test was not performed, use of Fragmin should be discontinued. Monitoring of anti-Xa activity. Monitoring the anticoagulant effect of Fragmin in most cases is not necessary, but it should be carried out in certain groups of patients: children, patients with renal failure, patients with insufficient or overweight, pregnant women, patients with an increased risk of bleeding or recurrent thrombosis. For laboratory monitoring of treatment with Fragmin, tests should be used to determine anti-Xa activity using a chromogenic substrate. It is not practical to determine activated partial prothrombin time or thrombin time, since these tests are insensitive to the activity of dalteparin. Increasing the dose of dalteparin to increase the activated partial prothrombin time may result in bleeding. Interchangeability with other anticoagulants. Fragmin is not interchangeable (in the same units) with unfractionated heparin, other low molecular weight heparins or synthetic polysaccharides. Each of these drugs differs in raw materials, manufacturing processes, physicochemical, biological and clinical properties, which determines the difference in their biochemical properties, dosing, clinical effectiveness and safety. Each of these drugs is unique and has its own instructions for use. Application in pediatrics. Given the insufficient experience with the use of the drug in children, the level of anti-Xa activity should always be determined in this category of patients. During pregnancy and breastfeeding. When using Fragmin during pregnancy, the likelihood of harm to the fetus is low. However, since the possibility of harmful effects on the fetus cannot be completely excluded, the drug should be prescribed during pregnancy only if absolutely necessary. Limited data are available on the excretion of dalteparin into breast milk. One study of 15 breastfeeding mothers who received prophylactic doses of dalteparin found negligible levels of anti-Xa activity in breast milk (breast milk to plasma concentration ratio ≤0.025–0.224). Although the oral absorption of low molecular weight heparins is negligible, limited clinical data do not allow conclusions to be drawn regarding the effect of this small level of anticoagulant activity in the nursing infant. The effect of dalteparin on the ability to drive vehicles and operate machinery has not been studied .

Fragmin