Fragmin Solution, syringe, 10 pcs, 0.3 ml, 7500 IU, for intravenous and subcutaneous administration

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.

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

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

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®

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 with 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.

The installation or removal of an epidural or spinal catheter should be carried out 10-12 hours after the last dose of dalteparin sodium when preventing venous thromboembolic complications; in individuals receiving higher therapeutic doses of dalteparin sodium (100-120 IU/kg every 12 hours or 200 IU/kg once daily), this interval should be at least 24 hours. The patient should be monitored extremely closely at periodic intervals to identify any symptoms or signs of neurological impairment (eg, numbness or weakness in the legs, bowel or bladder dysfunction).

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

It is recommended to monitor the platelet count in patients before starting Fragmin® therapy, and then regularly throughout the treatment period. 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 vitro test is recommended

for antiplatelet antibodies in the presence of heparin or low molecular weight heparins.
If the result of this in vitro
is positive or equivocal, or no testing has been performed at all, then treatment with Fragmin® should be discontinued (see section "Contraindications").

Fragmin® causes only a temporary prolongation of activated partial thromboplastin time (aPTT) and thrombin time. Accordingly, increasing the dose of the drug in order to prolong the aPTT may lead to overdose and bleeding. Prolongation of the aPTT should only be considered as a sign of an overdose of the drug Fragmin®.

To assess the anticoagulant activity of the drug Fragmin®, the method of choice is the determination of anti-Xa activity by a chromogenic method. In this case, tests to determine aPTT and thrombin time should not be used, since 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").

Monitoring the anticoagulant activity of Fragmin® is usually not necessary, but may be necessary in the treatment of special groups of patients: children, patients with renal failure, patients with low body weight or obesity, pregnant women, and patients with an increased risk of bleeding or relapse thromboembolism.

As with all anticoagulants, there is a risk of systemic bleeding when taking dalteparin sodium. Caution should be exercised when treating patients with high doses of dalteparin sodium after surgery. After initiation of treatment, it is necessary to constantly monitor the possible development of bleeding in the patient through regular physical examination of the patient, careful examination of wound discharge and periodic determination of hemoglobin levels and anti-Xa activity.

Blood samples for analysis of the activity of Fragmin® 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).

Fragmin®, like other low molecular weight heparins, can suppress adrenal secretion of aldosterone, leading to hyperkalemia, especially in patients with type II diabetes mellitus, chronic renal failure, metabolic acidosis, elevated blood potassium concentrations or using potassium-sparing drugs. Monitoring of potassium in the blood is necessary in patients at risk.

The units of action of Fragmin®, unfractionated heparin, other low molecular weight heparins and synthetic polysaccharides are not equivalent, therefore, if it is necessary to replace one drug with another, a dose adjustment is required.

Long-term heparin therapy is known to be associated with a risk of osteoporosis. Although a similar effect was not observed with Fragmin®, the risk of osteoporosis cannot be excluded.

In patients with severe acute or chronic renal failure (creatinine clearance less than 30 ml/min), administration of dalteparin sodium at a prophylactic dose of 5,000 IU once daily does not lead to excessive anticoagulation due to the lack of bioaccumulation and, therefore, does not increase the risk of bleeding.

It is impossible to assess the effectiveness and safety of using the drug Fragmin® for the prevention of thrombosis of artificial heart valves, therefore the use of Fragmin® for this purpose is not recommended.

In patients with severe liver dysfunction, it is necessary to reduce the dose of Fragmin®, as well as regular monitoring of anti-Xa activity.

In patients on hemodialysis, minor dose adjustments of Fragmin® are usually required, as well as monitoring of anti-Xa activity.

There is no need to discontinue Fragmin® in patients with ST-segment elevation myocardial infarction and if there are indications for thrombolytic therapy.

Elderly patients (especially patients over 80 years of age) have an increased risk of bleeding when using Fragmin® in therapeutic doses. Therefore, careful monitoring is recommended.

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.

Fragmin 2500IU/0.2ml 10 pcs. injection solution vetter pharma-fertigung

pharmachologic effect

Anticoagulant.

Composition and release form Fragmin 2500me/0.2ml 10 pcs. injection solution vetter pharma-fertigung

Solution for injection - 0.2 ml:

• active ingredients: dalteparin sodium - 2500 IU;
• excipients: water for injection; sodium chloride; sodium hydroxide or hydrochloric acid qs.

In disposable syringes of 0.2 ml; in a blister of 5 pcs.; There are 2 blisters in a cardboard pack.

Description of the dosage form

Transparent, colorless or yellowish solution.

Characteristic

Low molecular weight heparin isolated through the controlled depolymerization (with nitrous acid) of sodium heparin from the mucous membrane 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; the degree of sulfation is 2–2.5 per disaccharide.

Directions for use and doses

S/c, intravenous (stream or drip).

Fragmin cannot be administered intramuscularly!

In the treatment of acute deep vein thrombosis and pulmonary embolism - subcutaneously, 200 IU/kg once a day or 100 IU/kg 2 times a day. Monitoring of anticoagulant activity may not be necessary, but it should be kept in mind that it may be required when treating special groups of patients. The recommended plasma Cmax should be 0.5–1 IU anti-Xa/ml. 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.

To prevent blood clotting in the extracorporeal circulatory system during hemodialysis or hemofiltration - intravenously, choosing a dosage regimen from those given below.

Patients with chronic renal failure or those not at risk for bleeding usually require minor dosage adjustments, so frequent monitoring of anti-Xa levels is not necessary in most patients. When recommended doses are administered during hemodialysis, a plasma level of 0.5–1 IU anti-Xa/ml is usually achieved.

If the duration of hemodialysis or hemofiltration is less than 4 hours, a single intravenous bolus dose of 5000 IU can be used, or the regimen can be used as for procedures lasting more than 4 hours.

If the duration of hemodialysis or hemofiltration is more than 4 hours, 30–40 IU/kg is given intravenously, followed by an intravenous drip of 10–15 IU/kg/hour.

For patients with acute renal failure or patients with a high risk of bleeding - 5-10 IU/kg intravenously, followed by intravenous drips 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.

To prevent thrombus formation during surgical interventions - s.c. 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 operations in general surgical practice: patients with a risk of developing thromboembolic complications - s.c. 2500 IU 2 hours before surgery, then after surgery - s.c. 2500 IU / day (every morning) for the entire period while the patient is in on bed rest (usually 5–7 days); For patients with additional risk factors for the development of thromboembolic complications (for example, 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).

1. When starting therapy the day 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, 5000 IU is administered s.c. every morning.

When performing orthopedic operations (for example, during hip replacement operations), Fragmin should be administered up to 5 weeks after surgery, choosing one of the dosage regimens given 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.

In unstable angina and myocardial infarction (without a Q wave on the ECG), monitoring of anticoagulant activity is usually not required, but it should be borne in mind that it may be required in the treatment of special groups of patients. 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 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 physician). 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.

Pharmacodynamics

The anticoagulant effect is primarily due to the inhibition of factor Xa, with little effect on blood clotting time. Has little effect on platelet adhesion, i.e. has little effect on primary hemostasis.

Pharmacokinetics

Bioavailability after subcutaneous administration is approximately 90%; pharmacokinetic parameters are independent of dose. After intravenous administration of the drug, T1/2 is 2 hours, after subcutaneous administration - 3–5 hours. In patients with uremia, T1/2 of the drug increases. It is excreted mainly by the kidneys.

Indications for use Fragmin 2500me/0.2ml 10 pcs. injection solution vetter pharma-fertigung

Acute deep vein thrombosis, pulmonary embolism, unstable angina and myocardial infarction (without Q wave on ECG); prevention of blood coagulation in the extracorporeal circulatory system during hemodialysis and hemofiltration (in patients with acute and chronic renal failure), prevention of thrombus formation during surgical (including orthopedic) interventions.

Contraindications

Hypersensitivity to dalteparin sodium (including other low molecular weight heparins and heparin), immune thrombocytopenia (caused by a history of heparin or suspected presence), bleeding (clinically significant, for example from the gastrointestinal tract against the background of gastric or duodenal ulcer, intracranial bleeding), severe hypocoagulation, disorders of the blood coagulation system, septic endocarditis, recent injuries or surgical interventions on the central nervous system, organs of vision and hearing; planned spinal or epidural anesthesia or other procedures accompanied by lumbar puncture (this applies to high doses of Fragmin).

Application Fragmin 2500me/0.2ml 10 pcs. injection solution vetter pharma-fertigung during pregnancy and lactation

It may be used during pregnancy if the expected effect of therapy outweighs the potential risk to the fetus.

It has not been established whether Fragmin is excreted into breast milk.

special instructions

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.

Information on the effectiveness and safety of Fragmin in pediatrics is limited. If such use is necessary, anti-Xa levels should be monitored.

When receiving epidural or spinal anesthesia or performing a spinal tap in patients who are receiving anticoagulant therapy, or who are scheduled to receive 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 test is positive or equivocal, or no testing has been done at all, then treatment with Fragmin should be discontinued.

Monitoring the anticoagulant activity of Fragmin is usually not necessary, but 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 the maximum concentration of the drug in the blood 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.

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.

Overdose

Symptoms: bleeding.

Treatment: administration of protamine (1 mg inhibits 100 IU of dalteparin).

Side effects Fragmin 2500m/0.2ml 10 pcs. injection solution vetter pharma-fertigung

On average, 1% of patients have 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 hepatic transaminases (AST, ALT).

In several cases - immune thrombocytopenia (with or without thrombotic complications), skin necrosis, anaphylactic reactions, development of spinal or epidural hematoma.

Drug 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; combined use with antihistamines, cardiac glycosides, tetracyclines, and ascorbic acid weakens the effect of dalteparin.

Compatible with solutions for intravenous administration. Fragmin is compatible with isotonic sodium chloride solution (9 mg/ml) and isotonic dextrose solution (50 mg/ml).

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 .

Instructions for use FRAGMIN

Fragmin should not be administered intramuscularly. Due to the risk of hematoma, IM administration of other drugs should be avoided if the dose of dalteparin sodium in 24 hours exceeds 5000 IU.

Risk of bleeding

Fragmin should be used with caution in patients with thrombocytopenia and impaired platelet function, severe hepatic and renal failure, uncontrolled hypertension, hypertensive or diabetic retinopathy and known hypersensitivity to heparin and/or low molecular weight heparins. Caution should also be exercised when using high doses of dalteparin (eg, doses required for the treatment of acute deep vein thrombosis, pulmonary embolism and acute coronary artery disease) in recently operated patients, as well as in patients with other conditions with a possible increased risk of bleeding.

If a patient suffering from acute ischemic disease (unstable angina and non-Q wave myocardial infarction) develops myocardial infarction, thrombolytic therapy may be required. This does not mean that dalteparin therapy should be discontinued, but it does mean that there is an increased risk of bleeding.

Epidural and spinal anesthesia

When performing neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture while using low molecular weight heparins in patients (including patients planned to use anticoagulants), the risk of epidural or spinal hematoma increases, which can cause neurological complications of varying severity, including long-term or persistent paralysis. The risk of these complications increases with the use of indwelling epidural catheters after surgery or with concomitant use of medications that affect hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants. The risk also increases with traumatic or repeated epidural or lumbar punctures. Patients should be monitored frequently for the development of signs and symptoms of neurological impairment when anticoagulant therapy is administered in conjunction with epidural/spinal anesthesia.

In order to reduce the risk of bleeding during spinal or epidural anesthesia while using Fragmin, it is better to insert or remove a catheter at the moment when the anticoagulant effect of the drug is least pronounced. Insertion or removal of catheter should be delayed 10-12 hours after the last dose of Fragmin prescribed for thrombosis prophylaxis while patients receiving higher therapeutic doses of dalteparin (such as 100-120 IU/kg every 12 hours or 200 IU /kg 1 time/day), the minimum interval should be 24 hours. Performing epidural/spinal anesthesia or spinal puncture during the treatment of deep vein thrombosis with anticoagulants is contraindicated. After removal of the catheter, the next dose of Fragmin should be administered no earlier than 4 hours later.

When prescribing an anticoagulant to a patient prior to epidural/spinal anesthesia or spinal tap, extreme caution and close and frequent monitoring should be performed for signs or symptoms of nervous system involvement, such as back pain, sensory or motor disturbances (numbness or weakness of the lower extremities), and bowel or bladder dysfunction. Nursing staff should be able to recognize symptoms of nervous system damage at an early stage. Patients should be advised to report the occurrence of neurological symptoms to their physician. If signs or symptoms of a possible intraspinal hematoma appear, immediate diagnostic and therapeutic procedures, including spinal cord decompression, are necessary.

Artificial heart valves

Appropriate studies have not been conducted to evaluate the safety and effectiveness of Fragmin as a prophylaxis for valve thrombosis in patients with artificial heart valves. Prophylactic doses of Fragmin are not sufficient to prevent valve thrombosis in patients with artificial heart valves. The use of Fragmin cannot be recommended for this purpose.

Thrombocytopenia

Due to the risk of thrombocytopenia, it is recommended to determine the platelet count before starting treatment with dalteparin and regularly during treatment. Particular caution is required in patients with rapidly developing thrombocytopenia or severe thrombocytopenia (<100,000/mcL) associated with positive or unknown in vitro platelet antibody test results in the presence of dalteparin or other low molecular weight heparins and/or unfractionated heparins.

If thrombocytopenia occurs, treatment should be discontinued. Subsequently, treatment should be initiated with fractionated heparin, which did not cause aggregation of the patient's platelets in an in vitro aggregation study. In the future, the platelet count should be determined at least 2 times a week, especially during the first 3 weeks.

It is important to note that heparin-induced thrombocytopenia type II should not be confused with early postoperative thrombocytopenia.

Monitoring Anti-Xa Levels

Monitoring for the anticoagulant effect of dalteparin is generally not required but may be considered in special patient populations, such as children, patients with renal impairment, patients with very low body weight or morbid obesity, pregnant women, or patients at increased risk of bleeding or recurrence. thrombosis

The time required for clot formation, defined as aPTT, is the only indicator that is moderately prolonged by dalteparin treatment and should not be used because it is relatively insensitive to the effects of dalteparin. Therefore, increasing the dose in order to prolong the aPTT may lead to drug overdose and bleeding. For laboratory monitoring of the risk of bleeding, it is recommended to use functional methods for determining the level of anti-Xa.

Hyperkalemia, renal failure

Heparin may suppress adrenal aldosterone secretion and lead to hyperkalemia, especially in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, elevated plasma potassium levels, or in patients taking potassium-sparing drugs. The risk of hyperkalemia increases with increasing duration of therapy, but is usually reversible. In patients at risk, plasma potassium levels should be measured before starting heparin therapy and monitored regularly thereafter, especially if treatment lasts more than 7 days. In patients receiving dalteparin and undergoing chronic hemodialysis, dose adjustment and, as a result, monitoring of anti-Xa levels in the blood is required less frequently. In patients undergoing emergency hemodialysis, the pharmacokinetics of dalteparin may be more unstable and their therapeutic index may be narrowed. More careful monitoring of anti-Xa levels in these patients is necessary.

For long-term treatment of acute ischemic heart disease, for example, before revascularization, the need for dose reduction should be assessed in case of reduced renal function (serum creatinine level >150 µmol/l).

Interchangeability with other anticoagulants

The biological activity of various low molecular weight heparins, unfractionated heparin or synthetic polysaccharides cannot be determined using a test that simply compares doses of different drugs. Due to the fact that different low molecular weight heparins have different properties, their doses require adjustment. Thus, using one anticoagulant drug instead of another should be done with extreme caution and guided by the approved instructions for use of each specific drug.

Use in elderly patients

In elderly patients (especially patients aged 80 years and older), the risk of bleeding may be increased when using therapeutic doses of the drug. The clinical condition of such patients should be carefully monitored.

Use in pediatrics

Clinical experience in treating children is limited. When using dalteparin in children, monitoring of anti-Xa levels is necessary.

Preclinical safety data

The degree of acute toxicity is significantly lower with dalteparin sodium compared to heparin. In toxicology studies, local bleeding at the injection site was the only significant reaction regularly reported following high-dose subcutaneous administration of the drug. The frequency and severity of this phenomenon were dose-related. There was no cumulative effect on injection site bleeding.

Hemorrhagic reactions led to dose-dependent changes in the anticoagulant effect, which was assessed by measuring APTT and anti-Xa activity.

The osteoporotic effect of dalteparin sodium does not exceed that of heparin.

The study results did not reveal organotoxicity, regardless of the method of drug administration, dose and duration of therapy. No mutagenic effect was detected. No embryotoxic or teratogenic effects were observed; no effects on fertility or peri- or postnatal development were noted.

Impact on the ability to drive vehicles and operate machinery

Fragmin does not affect the ability to drive vehicles or operate mechanical equipment.