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Instruction for use: Fraxiparine
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Dosage form: Solution for subcutaneous administration
Active substance: Nadroparinum calcium
ATX
B01AB06 Nadroparin
Pharmacological group
Anticoagulants
The nosological classification (ICD-10)
I20.0 Unstable angina: heberden disease; Angina pectoris; The attack of angina pectoris; recurrent angina; Spontaneous angina; Stable angina pectoris; Angina rest; Angina progressing; Angina mixed; Angina spontaneous; stable angina; Chronic stable angina; Angina Syndrome X
I21.9 Acute myocardial infarction, unspecified: Changes in left ventricle with myocardial infarction; Changes in the left atrium with myocardial infarction; Myocardial infarction; Myocardial infarction without Q wave; Myocardial infarction without signs of chronic heart failure; Myocardial infarction with unstable angina; Pirouette tachycardia with myocardial infarction
I82.9 Embolism and thrombosis of unspecified vein: Venous embolism; Venous thrombosis; Diseases caused by blood clots in the vessels; Acute vascular occlusion; Acute venous thrombosis; Acute thrombosis of veins; Thrombosis; Thromboembolism; Phlebothrombosis; Embolism
Z49.1 Aids that include extracorporeal dialysis: hemodialysis; Chronic hemodialysis; Extracorporeal circulation; Thrombosis of hemodialysis shunt
Composition and release form
Solution for injection 1 syringe
Supraparin calcium IU anti-Ha 2850
Excipients: calcium hydroxide solution - q.s. (Or dilute hydrochloric acid) to pH 5.0-7.5; Water for injection - q.s. Up to 0.3 ml
In a blister 2 syringes disposable for 0.3 ml; In a box of cardboard 1 or 5 blisters.
Solution for injection 1 syringe
Supraparin calcium IU anti-Xa 3800
Excipients: calcium hydroxide solution - q.s. (Or diluted hydrochloric acid) to a pH of 5.0-7.5; Water for injection - q.s. Up to 0.4 ml
In a blister 2 syringes disposable in 0.4 ml; In a box of cardboard 1 or 5 blisters.
Solution for injection 1 syringe
Supraparin calcium, IU anti-Xa 5700
Excipients: calcium hydroxide solution - q.s. (Or diluted hydrochloric acid) to a pH of 5.0-7.5; Water for injection - q.s. Up to 0,6 ml
In a blister 2 syringes disposable for 0.6 ml; In a box of cardboard 1 or 5 blisters.
Solution for injection 1 syringe
Supraparin calcium, IU anti-Ha 7600
Excipients: calcium hydroxide solution - q.s. (Or diluted hydrochloric acid) to a pH of 5.0-7.5; Water for injection - q.s. Up to 0.8 ml
In a blister 2 syringes disposable for 0.6 ml; In a box of cardboard 1 or 5 blisters.
Solution for injection 1 syringe
Supraparin calcium, IU anti-Ha 9500
Excipients: calcium hydroxide solution - q.s. (Or diluted hydrochloric acid) to a pH of 5.0-7.5; Water for injection - q.s. Up to 1 ml
In a blister 2 syringes disposable 1 ml each; In a box of cardboard 1 or 5 blisters.
Description of dosage form
Transparent, slightly opalescent, colorless or light yellow solution.
Characteristic
Low molecular weight heparin (LMWH).
Pharmachologic effect
Mode of action - Anticoagulant, antithrombotic.
Pharmacodynamics
Nadroparin calcium is characterized by a higher anti-Xa factor in comparison with anti-IIa factor or antithrombotic activity. The ratio between the two activities for supraparin is in the range 2.5-4.
In preventive doses, supra -parrin does not cause a marked decrease in activated partial thrombin time (activated partial thromboplastin time).
At course treatment during the period of maximum activity, the activated partial thromboplastin time can be extended to a value 1.4 times higher than the standard one. This prolongation reflects the residual antithrombotic effect of the calcium supraparin.
Pharmacokinetic
Pharmacokinetic properties are determined on the basis of a change in the anti-Xa plasma activity factor. After the SC administration almost 100% of the drug is rapidly absorbed. Cmax in plasma is achieved between 3 and 4 hours, if supraparin calcium is used in a mode of 2 injections per day. With the application of calcium supra-paparin in mode 1, Cmax injection per day is achieved between 4 and 6 hours after administration. Metabolism occurs mainly in the liver (desulphation, depolymerization). After sc administration of T1 / 2, the anti-Xa factor activity of low molecular weight heparins is higher than in the case of unfractionated heparins and is 3-4 h.
As for anti-IIa factor activity, when low molecular weight heparins are used, it disappears from the plasma faster than anti-Xa factor activity.
Excretion occurs primarily by the kidneys, in the initial or little-changed form.
Risk groups
In elderly patients, since renal function is physiologically reduced, elimination is slowed down. This does not affect the dose and mode of administration of the drug for prophylactic purposes, as long as the renal function of these patients remains within acceptable limits, i.e. Is broken insignificantly.
Prior to treatment, LMWH should systematically assess the renal function of elderly patients over the age of 75 using the Cockcroft formula.
Weak to moderate renal failure (Cl> 30 mL / min): in some cases it may be useful to monitor the level of anti-Xa factor activity in the blood to exclude the possibility of an overdose in the course of the drug.
Hemodialysis: low-molecular-weight heparin is injected into the arterial line of the dialysis loops in high enough doses in order to prevent coagulation in the loop. In principle, the pharmacokinetic parameters do not change, except in the case of an overdose, when the passage of the drug into the systemic circulation may lead to an increase in anti-Xa factor activity associated with the final phase of renal failure.
Indication of the drug Fraxiparine
Prevention of thrombus formation during surgical interventions, blood clotting in the extracorporeal circulation system during hemodialysis or hemofiltration, thromboembolic complications in patients with a high risk of thrombosis (in acute respiratory and / or heart failure in intensive care settings).
Treatment of thromboembolism, unstable angina and myocardial infarction without a Q wave.
Contraindications
Hypersensitivity (including thrombocytopenia) to Fraksiparinu or other LMWH and / or heparin in the anamnesis; Signs of bleeding or an increased risk of bleeding associated with hemostasis, with the exception of the DIC syndrome not caused by heparin; Organic organ damage with a tendency to bleeding (eg, acute ulcer of the stomach or duodenum); Trauma or surgical intervention on the central nervous system; Septic endocarditis.
Pregnancy and breast-feeding
Experiments on animals did not show a teratogenic effect of calcium supraparin, however, in the first trimester of pregnancy, it is preferable to avoid the use of Fraxiparine in both the prophylactic dose and in the form of a course treatment.
During the second and third trimesters of pregnancy, Fraxiparine can only be used in accordance with the doctor's recommendations for the prevention of venous thrombosis (when comparing the benefits for the mother with the risk for the fetus). Course treatment in this period is not used.
If there is a question about the use of epidural anesthesia, it is recommended, as far as possible, to suspend preventive treatment with heparin, at least 12 hours before anesthesia.
Since absorption of the drug in the digestive tract in newborns is in principle unlikely, treatment with Fraxiparine of nursing mothers is not contraindicated.
Side effects
The most common side effect is the formation of subcutaneous hematoma at the injection site. In some cases there is the appearance of dense nodules, not meaning the encapsulation of heparin, which disappear after a few days.
Large doses of Fraxiparine can provoke bleeding of various localizations and mild thrombocytopenia (type I), which usually disappears in the course of further therapy. A temporary moderate increase in the level of hepatic enzymes (ALT, AST) is possible.
Necrosis of the skin and allergic reactions occur rarely. Several cases of anaphylactic reactions and immune thrombocytopenia (type II), combined with arterial and / or venous thrombosis or thromboembolism, have been reported.
Interaction
The development of hyperkalemia may depend on the simultaneous presence of several risk factors. Drugs that cause hyperkalemia: potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor blockers, NSAIDs, heparins (low molecular or unfractionated), cyclosporin and tacrolimus, trimethoprim. The risk of developing hyperkalemia increases with the combination of the aforementioned agents with Fraxiparine.
The combined use of Fraxiparine with such preparations that affect hemostasis, like acetylsalicylic acid, NSAIDs, vitamin K antagonists, fibrinolytic and dextran, leads to mutual enhancement of the effect.
In addition, it should be taken into account that inhibitors of platelet aggregation (in addition to acetylsalicylic acid as an analgesic and antipyretic drug, ie, in a dose exceeding 500 mg): NSAID, abciximab, acetylsalicylic acid in antiplatelet doses (50-300 mg) at Cardiac and neurological indications, beraprost, clopidogrel, eptifibatid, iloprost, ticlopidine, tirofiban increase the risk of bleeding.
Dosing and Administration
SC (except for use in the process of hemodialysis).
This form is for adults.
Not enter IV!
1 ml of fracsyparin is equivalent to approximately 9,500 IU of anti-Xa factor activity of supraparin.
Technique of the introduction
Preferably, the patient is administered in the prone position, subcutaneous tissue of the anterolateral or posterolateral abdominal belt, alternately from the right and left sides.
The needle should be inserted perpendicularly (and not at an angle) into the pinched skin fold, between the thumb and index finger until the end of the solution. Graduated syringes are designed to adjust the dose depending on the weight of the patient's body.
Preventive maintenance of thromboembolism in surgery
These recommendations refer to surgical procedures conducted under general anesthesia.
Frequency of application. 1 injection per day.
The dose applied. The dose is due to an individual level of risk, depending on the patient's body weight and type of operation.
Situations with moderate thrombogenic risk. In surgical operations representing moderate thrombogenic risk, as well as in patients without an increased risk of thromboembolism, effective prevention of thromboembolic disease is achieved by administering a dose of 2850 IU of anti-Xa factor activity per day (0.3 ml).
Initial injection should be administered 2 hours before surgery.
Situations with increased thrombogenic risk. Operations on the hip and knee: dosage of supra-papyrus depends on the weight of the patient's body. Enter 1 time per day: 38 IU of anti-Xa factor activity / kg before surgery, i.e. 12 hours before the procedure, after the operation, i.e. Starting from 12 hours after the end of the procedure, then per day, until the third day after the operation, inclusive; 57 IU anti-Xa factor activity / kg, starting from the fourth day after surgery.
Doses used in patients, depending on body weight, are as follows:
| Body weight of the patient, kg | Fraksiparin volume, administered once a day before the surgery and up to the third day after the operation, ml | Fraksiparin volume, administered once a day, starting from the fourth day after the operation, ml |
| <51 | 0,2 | 0,3 |
| 5170 | 0,3 | 0,4 |
| ≥70 | 0,4 | 0,6 |
In general surgery, LMWH treatment should last less than 10 days, in the absence of a special risk of venous thromboembolism associated with the individual characteristics of the patient (see "Special instructions").
If the risk of thromboembolic complications is present after the end of the recommended treatment period, it is necessary to continue preventive treatment, primarily with oral anticoagulants.
However, the clinical benefit of long-term treatment with low molecular weight heparins or vitamin K antagonists has not been evaluated to date.
Prevention of blood coagulation in the system of extracorporeal circulation in hemodialysis: intravascular (in the arterial shunt of the dialysis loop).
In patients receiving repeated hemodialysis sessions, the prevention of coagulation in the extracorporeal purification loop is achieved by administering an initial dose of 65 IU / kg to the arterial line of the dialysis loop at the beginning of the session.
This dose, used as a single intravascular bolus injection, is only suitable for dialysis sessions lasting no more than 4 hours. Subsequently, the dose may be set depending on the patient's individual response, which varies to a large extent.
Doses used in patients, depending on body weight, are as follows:
| Body weight of the patient, kg | Fraxiparine volume per dialysis session, ml |
| <51 | 0,3 |
| 5170 | 0,4 |
| ≥70 | 0,6 |
Any suspicion must immediately be confirmed by the results of the relevant analyzes.
Frequency of application. 2 injections per day with an interval of 12 hours.
The dose applied. The dose of each injection is 85 IU of anti-Xa factor activity / kg.
The dosage of LMWH has not been studied depending on the body weight of patients weighing more than 100 kg or less than 40 kg. In patients with a body weight of more than 100 kg, the effectiveness of LMWH can be reduced. On the other hand, in patients with a body weight of less than 40 kg, the risk of bleeding may increase. In such cases, special clinical control is required.
For this indication, the dose, applied depending on the weight of the patient, is 0.1 ml / 10 kg of body weight every 12 hours, as shown in the following table:
| Body weight of the patient, kg | Fraxiparine volume per administration, ml |
| 4049 | 0,4 |
| 5059 | 0,5 |
| 6069 | 0,6 |
| 7079 | 0,7 |
| 8089 | 0,8 |
| 9099 | 0,9 |
| ≥100 | 1,0 |
Frequency of application. Nadroparin calcium is used in the form of two SC injections per day (with an interval of 12 hours), each in a dose of 86 IU of anti-Xa factor activity, in combination with aspirin (recommended doses of 75-325 mg by mouth, after an introductory minimum dose of 160 mg ).
The dose applied. The initial dose should be administered as an IV bolus at a dose of 86 IU anti-Xa / kg, then sc, at the same dose.
Duration of treatment. The recommended duration of treatment is 6 days, until the patient's condition stabilizes in doses adjusted according to the body weight of the patient, as shown below:
| Body weight of the patient, kg | Introduced volume of Fraxiparin | |
| Initial dose (IV, bolus), ml | SC injection every 12 hours, ml | |
| <50 | 0,4 | 0,4 |
| 5059 | 0,5 | 0,5 |
| 6069 | 0,6 | 0,6 |
| 7079 | 0,7 | 0,7 |
| 8089 | 0,8 | 0,8 |
| 9099 | 0,9 | 0,9 |
| >100 | 1,0 | 1,0 |
Overdose
Accidental overdose with SC to the introduction of large doses of low molecular weight heparins can cause bleeding.
In case of ingestion - even a massive dose - of low molecular weight heparin (until now it has not been noted) serious consequences should not be expected, given the very low absorption of the drug.
Treatment: with small bleeding - delay the next dose.
In some cases, the use of protamine sulfate may be indicated, taking into account the following: its effectiveness is significantly lower than that described in connection with an overdose of unfractionated heparin; The ratio of the benefit / risk of protamine sulfate should be carefully evaluated, due to its side effects (in particular anaphylactic shock).
If it is decided to use such treatment, neutralization is carried out by slow intravenous administration of protamine sulfate.
The effective dose of protamine sulfate depends: on the administered dose of heparin (100 anti-heparin units protamine sulphate can be used to neutralize the activity of 100 IU anti-Xa factor activity of LMWH); The time elapsed after the administration of heparin, with a possible reduction in the dose of the antidote.
However, it is impossible to completely neutralize anti-Xa factor activity.
Moreover, the kinetics of absorption of low molecular weight heparin can give this neutralization a temporary character and require fragmentation of the total calculated dose of protamine sulfate into several injections (2-4) distributed per day.
Special instructions
Despite the fact that the concentration of various preparations of low molecular weight heparins is expressed in international units of anti-Xa factor activity, their effectiveness is not limited to anti-Xa factor activity. The replacement of the dosage regimen of one LMWH by another is dangerous and unacceptable. Each regimen was tested by special clinical trials. Therefore, special care is required and compliance with specific instructions for use for each drug.
Risk of bleeding. The recommended therapeutic regimens (dosages and duration of treatment) should be observed. In the opposite case, bleeding may occur, especially in patients at risk (elderly persons, patients suffering from kidney failure, etc.).
Serious bleeding was observed: in elderly patients, especially in connection with the weakening of kidney function with age; With renal insufficiency; In patients weighing less than 40 kg; In case of treatment duration exceeding recommended (10 days); In the case of non-compliance with the recommended treatment conditions (in particular, the duration and establishment of a dose based on body weight for the course application); When combined with drugs that increase the risk of bleeding.
In any case, special control is required in elderly patients and patients suffering from renal insufficiency, as well as when the drug is used for more than 10 days. In some cases, it may be useful to measure anti-Xa factor activity in order to detect accumulation of the drug.
The risk of heparin-induced thrombocytopenia (HIT). If a patient receiving treatment with LMWH (in course or prophylactic doses) has: a negative dynamics of thrombosis, for which the patient is treated, phlebitis, pulmonary embolism, acute ischemia of the lower extremities, myocardial infarction or stroke, they should be considered as Manifestation of heparin-induced thrombocytopenia (HIT), and an immediate analysis of the number of platelets.
Use in children. Due to the lack of data, the use of LMWH in children is not recommended.
Function of the kidneys. Before beginning treatment of LMWH, it is necessary to monitor kidney function, especially in elderly patients over the age of 75 years. The creatinine clearance is calculated by the Cockcroft formula and based on the actual body weight of the patient: in men, Cl creatinine = (140-age) × body weight / (0.814 × serum creatinine), expressed in years, body weight in kg, and serum creatinine in μmol / L (if creatinine is expressed in mg / ml, multiply by 8.8).
In women, this formula is supplemented by multiplying the result by 0.85.
The detection of severe renal failure (Cl creatinine about 30 ml / min) is a contraindication to the use of LMWH in the course form (see "Contraindications").
Laboratory testing
Control of the number of platelets
Heparin-induced thrombocytopenia
In connection with the danger of HIT development, it is necessary to control the number of platelets, regardless of the indication for use and the prescribed dose. Calculation of the number of platelets is performed before the start of treatment or no later than within the first day after the start of treatment, and then 2 times a week during the entire course of treatment.
The diagnosis of HIT should be assumed if the platelet count is <100,000 / mm3 and / or the platelet count falls by 30-50% relative to the previous analysis. It develops mainly between 5 and 21 days after the initiation of heparin treatment (with a maximum frequency of about 10 days).
However, it can appear much earlier in the presence of a patient with thrombocytopenia associated with heparin treatment, in very rare cases, and after 21 days. The collection of such anamnesis should be systematically carried out during the interview with the patient before the start of treatment. In addition, the risk of HIT with repeated administration of heparin may persist for several years or even indefinitely (see "Contraindications").
In any case, the emergence of GIT is an urgent situation and requires a consultation with a specialist. Any significant drop in the platelet count (by 30-50% of the initial value) should be considered as an alarm before reaching critical values. In case of a decrease in the number of platelets, it is necessary: immediately check the number of platelets.
Suspend the administration of heparin if the incidence is confirmed or detected with this control, in the absence of other obvious causes.
Select the blood sample in the citrate tube for the in vitro platelet aggregation assay and immunoassay. However, in such situations, urgent measures do not depend on the results of these analyzes, since these analyzes are carried out by only a few specialized laboratories, and at best the results can be obtained only after a few hours. Despite this, tests should be performed to establish an accurate diagnosis of the complication, because When continuing treatment with heparin, the risk of thrombosis is very high.
To prevent and treat thrombotic complications of GIT.
If complication occurs, anticoagulant treatment should be continued, heparin must be replaced by another class of antithrombotic drugs: danaparoid sodium or hirudin prescribed in preventive or curative doses, depending on the situation.
The substitution for vitamin K antagonists can be performed only after the normalization of the number of platelets, due to the risk of increased thrombotic effect.
The replacement of heparin with a vitamin K antagonist. In this case, clinical and laboratory controls should be strengthened to monitor the effects of the vitamin K antagonist.
Since the full action of the vitamin K antagonist is not immediately apparent, heparin should continue to be given in an equivalent dose, as long as it is necessary to achieve the required INR level in this test in two consecutive analyzes.
Control of anti-Xa factor activity. Since most of the clinical trials demonstrating the efficacy of LMWH have been conducted at doses adjusted for the patient's body weight and without any special laboratory control, the value of this type of monitoring for the evaluation of LMWH effectiveness is not established. However, laboratory monitoring by determining anti-Xa factor activity may be useful in the risk of bleeding in some clinical situations, often associated with the risk of overdose.
These situations may relate to indications for the course use of LMWH, in connection with the applied doses, with mild and moderate renal failure (Cl, calculated by Cockcroft's formula, 30-60 ml / min): in fact, unlike unfractionated standard heparin, LMWH is excreted primarily Kidneys, and impaired renal function can lead to a relative overdose. With regard to severe renal failure, it is a contraindication to the use of LMWH in the exchange rate regime (see "Contraindications"); With extreme body weight (reduced body weight or even exhaustion, obesity); With unexplained bleeding.
However, laboratory monitoring is not recommended when using prophylactic doses, if LMWH treatment is in line with recommendations (especially with regard to duration) and hemodialysis.
In order to identify possible cumulation after repeated administration, it is recommended to take blood from the patient whenever possible at the maximum activity of the drug (in accordance with the available data), ie:
Approximately 4 hours after the third administration if the drug is administered in the form of two SC injections per day or approximately 4 hours after the second administration if the drug is administered in the form of one SC injection per day.
The repeated determination of anti-Xa factor activity for measuring serum heparin levels - every 2 or 3 days - should be considered in each individual case, depending on the results of the previous analysis, if necessary, modifying the dosage of LMWH.
For each LMWH and for each therapeutic regimen, the generated anti-Xa factor activity is different.
In accordance with the indications and according to the available data, the average anti-Xa factor activity (± standard deviation) observed at the fourth hour after the administration of supraparin in the dose:
83 IU / kg as two injections per day was 1.01 ± 0.18 IU
168 IU / kg as a single injection per day was 1.34 ± 0.15 IU
The mean value was observed during clinical trials to determine the anti-Xa factor activity performed using the chromogenic (amidolytic) method.
Activated partial thromboplastin time (APTT). Some LMWHs moderately extend the APTTV. (Has no clinical significance).
Performing spinal / epidural anesthesia in the case of prophylactic use of LMWH. When using LMWH, as well as other anticoagulants, during spinal or epidural anesthesia, there were rare cases of intraspinal hematoma leading to prolonged or persistent paralysis.
The risk of intraspinal hematoma appears to be higher when using an epidural catheter than with spinal anesthesia.
The risk of this rare complication may increase with prolonged use of the epidural catheter after surgery.
If preoperative treatment with LMWH is necessary (prolonged immobilization, trauma), and the advantages of spinal anesthesia are carefully evaluated, this technique can be used in a patient who received an injection of LMWH before surgery if a period of at least 12 hours has passed between the heparin injection and the application of the spinal cerebral anesthetic Due to the danger of intraspinal hematoma, a thorough neurological control is necessary.
In almost all cases, preventive treatment of LMWH can be initiated within 6-8 hours after the application of an anesthetic or catheter extraction, with neurological monitoring.
Particular care is required in the case of combination with other drugs that affect hemostasis (namely, NSAID, acetylsalicylic acid).
Does not affect the ability to drive and work on machines.
Use of the needle protection system: after administration of the drug, apply a safety system for the Fraxiparine syringe. Holding the used syringe in one hand by the protective casing, with the other hand pull the holder to release the latch and shift the cover to protect the needle until it clicks. The used needle is fully protected.
Manufacturer
Sanofi Winthrop Industry, France.
Storage conditions of the drug Fraxiparine
At a temperature not higher than 30 ° C.
Keep out of the reach of children.
The shelf life of the drug Fraxiparine
3 years.
Do not use beyond the expiration date printed on the package.
