FRAGMIN

Active material: Dalteparin sodium
When ATH: B01AB04
CCF: The anticoagulant of direct action – Heparin nizkomolyekulyarnyi
ICD-10 codes (testimony): I20.0, I21, i26, I74, I82
When CSF: 01.12.11.06.02
Manufacturer: PFIZER MFG. BELGIUM N.V. (Belgium)

Pharmaceutical form, composition and packaging

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

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

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

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

Excipients: sodium hydroxide or hydrochloric acid q.s., water d / and.

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

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

Excipients: water d / and.

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

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

Excipients: water d / and.

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

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

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

1 ml – ampoule (10) – packs cardboard.

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

Excipients: water d / and.

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

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

Excipients: water d / and.

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

The solution for I / O and p / to the introduction clear, colorless or yellowish brown.

Excipients: water d / and.

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

Pharmacological action

The anticoagulant of direct action. Is a low-molecular heparin, selected during controlled depolymerization (with nitrous acid) heparin sodium from mucous membrane of small intestine of the pig and subjected to additional cleaning by using ion-exchange chromatography. Consists of sulfated polisaharidnyh chains, with an average molecular weight 5000 Dalton; wherein 90% have a molecular weight of 2000 to 9000 Dalton; degree of sulfatirovanija – from 2 to 2.5 the disaccharide.

Binds Antithrombin plasma, as a result of which inhibits the activity of Factor Xa and Thrombin. Protivosvertawati effect of dalteparin preparations sodium primarily due to inhibition of Factor Xa; the clotting time affects slightly. Compared to heparin provides poor impact on leukocyte adhesion and, thus, has less impact on primary hemostasis.

Pharmacokinetics

Pharmacokinetic parameters dalteparin preparations sodium do not change depending on the imposed dosage.

Absorption

After p/to the introduction of the bioavailability of dalteparin preparations sodium is about 90%.

Deduction

T_1/2 After the on/in the introduction is 2 no, after s / to the introduction of – 3-5 no. Dalteparin sodium displayed mainly kidneys, However, the biological activity of fragments, urine output, poorly understood. In urine in less 5% anti-Xa activity. Clearance of anti-Xa activity of dalteparin preparations of plasma after a single on/in the introduction of the drug in the form of a bolus dose 30 and 120 ME (anti-Xa)/kg averaged 24.6 ± 5.4 and 15.6 ± 2.4 ml/HR/kg, respectively, a T_1/2 – 1.47± 0.3 and 2.5 ± 0.3 h.

Pharmacokinetics in special clinical situations

In patients with uremyei T_1/2 increases.

In patients with chronic renal insufficiency, receiving hemodialysis, After a single on/in the introduction of dalteparin preparations sodium dose 5000 ME T_1/2, formula on anti-HA activity, amounted to 5.7 ± 2 h and was significantly higher, than in healthy volunteers. Respectively, such patients can expect a more pronounced cumulation drug.

Testimony

— acute deep vein thrombosis;

-pulmonary embolism;

-Prevention of blood clotting in the extracorporeal circulation during hemodialysis or Hemofiltration in patients with acute or chronic renal failure;

Prevention tromboobrazovania with surgical interventions;

-Prevention of thromboembolic complications in patients with therapeutic disease in the acute phase and reduced mobility (incl. under conditions, requiring bed rest);

— unstable angina and myocardial infarction (without pathological zubza Q on ECG);

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

Dosage regimen

"FRAGMIN"^® You cannot enter in/m!

Treatment of acute deep vein thrombosis and pulmonary thromboembolism

"FRAGMIN"^® introduced n / a 1-2 times / day. You can immediately start therapy antikoagulyantami indirect (Vitamin K antagonists). Such combined therapy should be continued until, While the prothrombin index reaches therapeutic levels (usually no earlier than 5 days). Treatment of patients in an outpatient setting can be carried out in doses, recommended for therapy in the hospital.

When administered 1 times/day dose, component 200 IU / kg body weight, introduced n / a. A single dose should not exceed 18 000 ME. Monitoring in the anticoagulation activity of the drug may be dispensed.

When administered 2 times/day injected 100 IU/kg body weight p/. Monitoring in the anticoagulation activity of the drug may be dispensed, but it should be borne in mind, that this may be necessary when treating certain groups of patients. The recommended maximum concentration of the drug in plasma should be 0.5-1 IU anti-Xa/mL.

Prevention of blood clotting in the extracorporeal circulation during hemodialysis or Hemofiltration

"FRAGMIN"^® introducing / in.

Patients with chronic renal insufficiency, or patients without risk of bleeding, usually, need a small correction mode, so in most cases there is no need for frequent monitoring of the level of anti-HA. With the introduction of recommended doses during hemodialysis is usually achieved the level of anti-HA activity 0.5-1 IU / mL. At the duration of hemodialysis or Hemofiltration no more 4 no the drug is injected in/in struino for 30-40 IU/kg body weight followed by/in drip introduction with speed 10-15 IU/kg/h or momentary struino dose 5000 ME. At the duration of hemodialysis or Hemofiltration more 4 no spend/in a Jet drug dose based 30-40 IU/kg followed by/in drip introduction with speed 10-15 IU/kg/h.

When applying Fragmina^® in patients acute renal insufficiency or in patients with a high risk of bleeding the drug is injected in/in struino based 5-10 IU / kg, followed by/in drip introduction with speed 4-5 IU/kg/h. When carrying out the emergency hemodialysis (about acute renal failure) need more careful monitoring of anti-HA activity level, because the range of therapeutic doses for such patients much already, than for patients, on chronic hemodialysis. Recommended maximum anti-HA activity level in plasma should be within 0.2-0.4 IU / mL.

Prevention of thrombosis in surgical interventions

"FRAGMIN"^® introduced n / a. Monitoring in the anticoagulation activity, usually, not required. In applying the drug in the recommended doses (C)_max plasma ranging from 0.1 to 0.4 IU anti-Xa/mL.

At the operation in general surgery in patients at risk for thromboembolic complications product misleading s/to the dose 2500 IU for 2 hours before the operation, then after 2500 IU / day (every morning) during the entire period of, While the patient is on bedrest (usually 5-7 days).

Patients with additional risk factors for thromboembolic complications (incl. patients with malignant tumors) "FRAGMIN"^® should be applied over the entire period, While the patient is on bedrest (usually 5-7 days or more). While at the beginning of therapy the day before surgery "FRAGMIN"^® injected s / c in a dose of 5000 IU the night before the operation, then after 5000 IU every evening. At the beginning of therapy per day of operation enter n/a 2500 IU for 2 hours before the operation and 2500 IU a 8-12 no, but not earlier than 4 hours after the end of the operation,; then the next day every morning 5000 ME.

At conducting orthopedic operations (eg, During endoprosthetic replacement of the hip joint) "FRAGMIN"^® should be imposed for up to 5 weeks after surgery, selecting one of alternative dosing regimes. At the beginning of therapy, medication is injected in a dose 5000 IU p/night, on the eve of the operation, then 5000 IU every evening after surgery. At the beginning of therapy per day of operation "FRAGMIN"^® injected s / c in a dose of 2500 IU for 2 hours before the operation and 2500 IU a 8-12 no, but not earlier than 4 h after surgery; then the next day every morning – by 5000 ME.

At the beginning of therapy after the operation the drug enter n/a dose 2500 IU a 4-8 hours after surgery, but not earlier than 4 h after surgery; then the next day p/to 5000 IU / day.

Prevention of thromboembolic complications in patients with therapeutic disease in the acute phase and reduced mobility (incl. under conditions, requiring bed rest)

"FRAGMIN"^® should enter n/a on 5000 ME 1 times per day usually within 12-14 days or longer (in patients with continuing restriction of mobility). Monitoring in the anticoagulation activity, usually, not required.

Unstable angina or myocardial infarction without zubza Q pathological ECG

Monitoring in the anticoagulation activity, usually, not required, but it should be borne in mind, that he may need in the treatment of special groups of patients. Recommended C_max drug plasma must be 0.5-1 IU anti-Xa/mL (at the same time it is advisable to acetylsalicylic acid therapy at a dose of 75 to 325 mg / day). "FRAGMIN"^® Enter n/a on 120 IU / kg of body weight every 12 no. The maximum dose does not exceed 10 000 IU/12 h. Therapy should be continued until, until the clinical condition of the patient will not become stable (usually not less than 6 days) or longer (at the discretion of the physician). Then recommend move to long-term therapy Fragminom^® in a constant dose until the revascularization (through the skin or Aortocoronary bypass surgery). The total duration of therapy should not exceed 45 days.

Dose Fragmina^® selected on the basis of sex and body mass index patient. Women with body mass < 80 kg and males weighing < 70 kg the drug should enter n/a on 5000 IU every 12 no. Women weighing ≥ 80 kg and males weighing ≥ 70 kg must be entered on the 7500 IU p/every 12 no.

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

1 month – assign s/to the dose 200 IU / kg body weight 1 time / day. The maximum daily dose – 18 000 ME.

2-6 months – assign s/c in a dose of about 150 IU / kg body weight 1 time / day, using the fixed-dose syringes in accordance with table 1.

Table 1. The definition of dose Fragmina^® Depending on body weight, for a period of treatment 2-6 months.

At thrombocytopenia, developed on the background of chemotherapy, with a number of platelets < 50 000/l application Fragmina^® should be suspended until the increase in the number of platelets more 50 000/l. For platelet count from 50 000/l to 100 000/MCL dose must be reduced by 17-33% regarding the initial dose, Depending on the body weight of the patient in accordance with the table of 2. When restoring a platelet count to a level ≥ 100 000/MKL product should appoint full dose.

Table 2. Reducing the dose Fragmina^® for thrombocytopenia 50 000/MKL-000000/100 µl

Severe renal failure creatinine level greater than 3 times, exceeding VGN, dose Fragmina^® should be adjusted, to maintain a therapeutic level anti-HA 1 IU / mL (range 0.5-1.5 IU / mL), a formula for 4-6 hours after injection. If the level of anti-HA above or below therapeutic range, What dose Fragmina^® should therefore increase or decrease, anti-HA measurements should be repeated after the introduction 3-4 new doses. Correction dose should be held until a therapeutic level of anti-HA.

Side effect

Side effects are observed in average 1% patients.

On the part of the blood and blood coagulation: bleeding, hematoma at the injection site, reversible neimmunnaja thrombocytopenia, bleeding; in some cases – immune thrombocytopenia (with or without thrombotic complications); development of spinal or epidural hematoma, peritoneal and intracranial hemorrhage, some of them fatal.

From the digestive system: transient increase in liver transaminases (IS, GOLD).

Local reactions: soreness at the injection site; in some cases – skin necrosis.

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

Contraindications

-immune thrombocytopenia (caused by heparin) in history or suspected it;

-bleeding (clinically significant, eg, from the digestive tract against the backdrop of a peptic ulcer of a stomach and/or duodenal ulcer, intracranial hemorrhage);

— expressed violations on the part of blood coagulation;

- Bacterial endocarditis;

-recent injury or operational intervention CNS, organs of vision, hearing;

- Hypersensitivity to the drug;

-hypersensitivity to other molecular geparinam and/or geparino.

In connection with the increased risk of bleeding "FRAGMIN"^® high dose (applied, eg, for the treatment of acute deep vein thrombosis, pulmonary artery thromboembolism, unstable angina and myocardial infarction without zubza Q pathological ECG) do not assign patients, which planned spinal or epidural anesthesia, or other procedures, accompanied by lumbar puncture biopsy.

FROM caution, especially in patients in the early postoperative period, should appoint "FRAGMIN"^® high dose (eg, for the treatment of acute deep vein thrombosis, pulmonary artery thromboembolism, unstable angina and myocardial infarction without zubza Q on ECG); the caution should appoint "FRAGMIN"^® patients with a high risk of bleeding, incl. patients with thrombocytopenia, platelet function disorders, severe hepatic or renal failure, uncontrolled hypertension, hypertensive or diabetic retinopathy.

Pregnancy and lactation

When applying during pregnancy found no adverse effects on pregnancy, as well as the health of the fetus and newborn. When applying Fragmina^® during pregnancy, the risk of adverse effects on the fetus is assessed as low. However, because of the potential for adverse effects cannot be completely eliminated, "FRAGMIN"^® You can assign only on strict conditions, When the intended benefits to the mother outweighs the potential risk.

If you must use Fragmina^® during pregnancy should be monitored in the anticoagulation activity of.

IN experimental studies It is not revealed or teratogenic drug fetotoksicheskoe.

Not installed, whether dalteparin sodium is excreted in breast milk.

Cautions

The drug should not be administered i / m!

At carrying out of nejroaksialnoj anesthesia (epidural/spinal anesthesia) or when performing a lumbar puncture in patients, that receive anticoagulant therapy or who planned to pursue antikoagulyantnuu therapy using low molecular weight heparins for prevention of thromboembolic complications, There is an increased risk of spinal or epidural hematoma, that in turn could lead to a prolonged or permanent paralysis. The risk of such complications is increased when using regular epidural catheters for introduction of analgesics or while using drugs, affecting hemostasis (NSAIDs, inhibitors of platelet function, other anticoagulants). The risk also increases with injuries and repeated epidural or lumbar puncture. In such cases, patients should be kept under constant surveillance for early detection of abnormal neurological symptoms. When neurological disorders shows urgent decompression of the spinal cord.

There are no clinical data on the use of Fragmin^® When the pulmonary artery thromboembolism in patients with circulatory problems, arterial gipotenziei or shock.

With the rapid development of the therapy Fragminom^® thrombocytopenia or thrombocytopenia in the number of platelets less 100 000/l it is recommended to test for in vitro antiplatelet antibodies in the presence of heparin or low molecular weight heparins. If the results of the in vitro test are positive or dubious or no testing was conducted, the "FRAGMIN"^® should be abolished.

In monitoring in the anticoagulation activity Fragmina^®, usually, There is no need to. However, it should be carried out with the use of Fragmina^® children, patients with body weight below normal or obese, pregnant women, as well as high risk bleeding or re-thrombosis.

Taking samples of blood for analysis of Fragmina activity^® should be made between, When the maximum concentration of the drug in plasma (3-4 h after s / c injection).

To determine anti-HA activity method of choice are laboratory tests, that use a chromogenic substrate. You should not use the tests to determine the ACTV and Thrombin time, because these tests are relatively insensitive to the activity of dalteparin preparations sodium. Dose Fragmina^® to increase the APTT may cause bleeding.

Unit action Fragmina^®, unfractionated heparin or other low molecular weight heparins are not equivalent, Therefore, when replacing one drug with another is required to produce a correction dosage.

When you use multi-dose vials of unused solution should be destroyed through 14 days after the first piercing needle tube.

Use in Pediatrics

There is only limited information on the safety and effectiveness of Fragmina^® in pediatric practice. When applying Fragmina^® in children it is necessary to monitor the level of anti-HA activity.

Overdose

Symptoms: When excessive doses may develop haemorrhagic complications. Overdose is possible, in most cases, bleeding skin and mucous sheath, The intestine and urogenital tract. Lowering blood pressure, decrease in hematocrit and other symptoms may indicate a hidden bleeding.

Treatment: in the case of bleeding apply Fragmina^® should be suspended for evaluation of the severity of the bleeding and the risk of thrombosis.

Antikoagulyannetary effect Fragmina^® You can eliminate the introduction of protamine sulfate, non-urgent therapy tool. 1 mg protamine sulfate partially neutralizes the effect of 100 ME(anti-IIa) dalteparin preparations sodium (and, Although there had been a complete neutralization induced increase blood clotting time, from 25% to 50% anti-HA activity dalteparin preparations sodium still.

Drug Interactions

In an application with drugs, vliyayushtimi of gemostaz, such as tromboliticheskie tools (al′teplaza, streptokinase, urokynaza), indirect anticoagulants, Vitamin k antagonists, NSAIDs (incl. acetylsalicylic acid, Indomethacin), as well as inhibitors of platelet function, anticoagulant effect of Fragmina^® can be enhanced (increased risk of bleeding).

Pharmaceutical interaction

"FRAGMIN"^® compatible with izotoniceski solution of sodium chloride (9 mg / ml), izotoniceski solution of dextrose (Glucose) (50 mg / ml).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

Drug ampoules should be stored at a temperature of no higher than 30° c, in the injection – at a temperature no higher than 25 ° C. Shelf life – 3 year.

The drug should be stored out of reach of children.