Fraxiparine (Nadroparin calcium) syringes

The composition and form of issue:

Solution for injection 1 syringe

nadroparin calcium IU anti-XA 2850

auxiliary substances: calcium hydroxide solution q.s. (or diluted hydrochloric acid) to pH 5.0–7.5 water for injection — q.s. to 0.3 ml 

in blister of 2 disposable syringe of 0.3 ml per carton cartons 1 or 5 blisters.

Solution for injection 1 syringe

nadroparin calcium IU anti-XA 3800

auxiliary substances: calcium hydroxide solution q.s. (or diluted hydrochloric acid) to pH 5.0–7.5 water for injection — q.s. to 0.4 ml 

in blister of 2 disposable syringe 0.4 ml per carton cartons 1 or 5 blisters.

Solution for injection 1 syringe

nadroparin calcium, IU of anti-XA 5700

auxiliary substances: calcium hydroxide solution q.s. (or diluted hydrochloric acid) to pH 5.0–7.5 water for injection — q.s. to 0.6 ml 

in blister of 2 disposable syringe of 0.6 ml per carton cartons 1 or 5 blisters.

Solution for injection 1 syringe

nadroparin calcium, IU of anti-XA 7600

auxiliary substances: calcium hydroxide solution q.s. (or diluted hydrochloric acid) to pH 5.0–7.5 water for injection — q.s. to 0.8 ml 

in blister of 2 disposable syringe of 0.6 ml per carton cartons 1 or 5 blisters.

Solution for injection 1 syringe

nadroparin calcium, IU of anti-XA 9500

auxiliary substances: calcium hydroxide solution q.s. (or diluted hydrochloric acid) to pH 5.0–7.5 water for injection — q.s. to 1 ml 

the blister pack 2 syringe disposable 1 ml in a cardboard box 1 or 5 blisters.

Description pharmaceutical form:

Transparent, slightly opalescent, colorless or pale yellow solution.

Feature:

Low molecular weight heparin (LMWH).

Pharmacokinetics:

Pharmacokinetic properties are determined on the basis of changes in anti-XA factor activity in plasma. After p/to the introduction of almost 100% of the drug is rapidly absorbed. Cmax in plasma is reached between 3 and 4 hours if nadroparin calcium used in the regime of 2 injection a day. When applying nadroparina calcium in mode 1 injection a day, Cmax is achieved between 4 and 6 h after injection. Metabolism occurs mainly in the liver (desulfation, depolymerization). After p/to the introduction of the T1/2 of anti-XA factor activity low molecular weight heparins is higher than in the case of unfractionated and LMWH is 3-4 hours

As for anti-factor IIA activity, the application of low molecular weight heparins, it disappears from the plasma faster than the anti-XA factor activity.

Excretion is primarily by the kidneys, the source or malaisienne form.

Risk groups

In elderly patients, because renal function is physiologically reduced, elimination slows down. This does not affect the dose and mode of administration of prophylactic as long as the renal function of these patients remains within acceptable limits, i.e., broken slightly.

Prior to treatment, LMWH should be systematically evaluate the renal function of elderly patients aged over 75 years, using the formula Cockroft.

Mild to moderate renal insufficiency (Cl >30 ml/min): in some cases, it may be useful to control the level of anti-XA factor activity in the blood to exclude the possibility of an overdose in exchange application of the drug.

Hemodialysis: low-molecular heparin is injected into the arterial line of the dialysis loop at high enough doses to prevent blood clotting 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 systemic circulation can lead to an increase of anti-XA factor activity, associated with end phase renal failure.

Description pharmacological action:

Nadroparin calcium is characterized by higher anti-XA factor compared with anti-IIA factor or antithrombotic activity. The relationship between the two activities for nadroparin is in the range of 2.5–4.

Prophylactic doses of nadroparin does not cause decrease of activated partial thrombin time (APTT).

In the course of treatment in the period of maximum activity APTT can be extended to a value 1.4 times the standard. This extension reflects the residual antithrombotic effect of nadroparin of calcium.

Indications:

Prevention of thrombotic formation during surgery and blood clotting in the extracorporeal circulation during hemodialysis or hemofiltration, thromboembolic complications in patients with high risk of thrombosis (acute respiratory and/or cardiac failure in the conditions of intensive care units).

Treatment of thromboembolism, unstable angina and myocardial infarction without q wave.

Contraindications:

Hypersensitivity (including thrombocytopenia) to Fraxiparine or other LMWH and/or heparin in history signs of bleeding or increased risk of bleeding associated with violations of hemostasis, except for the DIC, not caused by heparin, organic lesions of organs with a tendency to bleeding (e.g. acute gastric ulcer or duodenal ulcer) trauma or surgery on the Central nervous system bacterial endocarditis.

Application of pregnancy and breast-feeding:

Experiments on animals have not shown teratogenic effect of nadroparin of calcium, however in the first trimester of pregnancy should preferably be avoided Fraxiparina as in a prophylactic dose, and in the form of a course of treatment.

During the II and III trimesters of pregnancy fraxiparin can only be used in accordance with doctor’s recommendations for prevention of venous thrombosis (when comparing the benefits to the mother risk to the fetus). Course treatment during this period does not apply.

If there is a question about the use of epidural anesthesia, it is recommended that, as far as possible, pause, prophylactic treatment with heparin at least 12 h before anesthesia.

Since the absorption of the drug in the gastrointestinal tract in newborns, in principle, unlikely, treatment Fraksiparinom nursing mothers is not contraindicated.

Side effects:

The most frequent side effect is the formation of subcutaneous hematoma at the injection site. In some cases there is the appearance of solid nodules, not meaning the encapsulation of heparin, which disappears in a few days.

Fraxiparina large doses can provoke bleeding of various localization and mild thrombocytopenia (type I), which usually disappears in the process of further therapy. May be a temporary moderate increase of liver enzymes levels (ALT, AST).

Necrosis of the skin and allergic reactions are rare. The number of reported cases of anaphylactic reactions and immune thrombocytopenia (type II), combined with arterial and/or venous thrombosis or thromboembolism.

Drug interactions:

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, blockers of angiotensin II receptors blockers, NSAIDs, heparins (low molecular or unfractionated), ciclosporin and tacrolimus, trimethoprim. The risk of hyperkalemia is increased when a combination of the above means Fraksiparinom.

The combined use Fraxiparine with such drugs that affect hemostasis, as acetylsalicylic acid, NSAIDs, vitamin K antagonists, fibrinolytic and dextran, leads to the mutual strengthening effect.

In addition, you should take into account that the thrombocyte aggregation inhibitors (except acetylsalicylic acid as analgesic and antipyretic drugs, i.e., in the dose of 500 mg): NSAIDs, abciximab, acetylsalicylic acid in antiplatelet doses (50-300 mg) in cardiac and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, tiklopidin, tirofiban increase the risk of bleeding.

Method of application and dose:

N/a (except for use in the process of hemodialysis).

This form is intended for adults.

Issue/m!

1 ml Fraxiparine equivalent to approximately 9500 IU anti-XA factor activity of nadroparin.

Equipment p/to the introduction

Preferably administered to the patient in the supine position, in the subcutaneous tissue of the anterolateral or posterolateral abdominal waist, alternately on the right and left sides.

The needle should enter perpendicular (not angled), pinched a fold of skin held between the thumb and index finger until the end of the administration of the solution. Graduated syringes are intended for the selection of doses depending on patient weight.

Prevention of thromboembolism in surgery

These recommendations apply to surgical procedures performed under General anesthesia.

The frequency of application. 1 injection per day.

The applied dose. The dose due to the individual level of risk, depending on patient weight and on the type of operation.

A situation with moderate thrombogenic risk. During surgery, representing a moderate thrombogenic risk and in patients without high risk of thromboembolism, effective prevention of thromboembolic disease is achieved by injection of a dose of 2850 IU anti-XA factor activity per day (0.3 ml).

The initial injection should be administered 2 hours before surgery.

Situation with a high thrombogenic risk. Hip surgery and knee: nadroparin dosage depends on patient weight. Administered 1 time per day: 38 IU anti-XA factor activity/kg before the surgery, ie for 12 hours before the procedure, after the operation, i.e. starting from 12 h after the procedure, then a day, until the third day after surgery, including 57 IU anti-XA factor activity/kg, starting from the fourth day after the operation.

Doses used in patients, depending on body mass, the following:

If necessary, the dose may be changed in accordance with each individual case and with the technical conditions of the dialysis. In patients with an increased risk of bleeding dialysis sessions may be conducted using half the dose.

Treatment of deep vein thrombosis (DVT)

Any suspicion should immediately be confirmed by the results of appropriate tests.

The frequency of application. 2 injection per day at intervals of 12 h.

The applied dose. The dose of each injection is 85 IU anti-XA factor activity/kg.

The dosage of LMWH has not been studied, depending on body weight patients with body weight over 100 kg or below 40 kg for patients with body weight more than 100 kg, the efficacy of LMWH can be reduced. On the other hand in patients with body weight less than 40 kg, the risk of bleeding may be increased. In such cases, require special clinical monitoring.

For this evidence the dose used depending on the patient weight, is 0.1 ml/10 kg of body weight every 12 h, as shown in the following table:

The duration of treatment. Treatment with LMWH should be quickly replaced by oral anticoagulants, except in those cases when the latter is contraindicated. The duration of LMWH treatment should not exceed 10 days, including the period of transition to antagonists of vitamin K (AVK), except in those cases when there are problems of stabilization of MNO (see “Special instructions”). Thus, treatment with oral anticoagulants should be initiated as early as possible.

Treatment of unstable angina/myocardial infarction without Q wave changes

The frequency of application. Nadroparin calcium used in form of two s/C injection per day (with an interval of 12 h), each in a dose of 86 IU anti-XA factor activity, in combination with aspirin (recommended dose 75-325 mg orally, after the initial minimum dose of 160 mg).

The applied dose. The initial dose should be entered as in/in the bolus at a dose of 86 IU anti-XA/kg, then n/a at the same dose.

The duration of treatment. The recommended duration of treatment is 6 days, until stabilization of the patient in doses adjusted according to body weight of the patient, as shown below:

Overdose:

Accidental overdose when s/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 (so far not mentioned) serious consequences not expected, given the very low absorption of the drug.

Treatment the small bleeding delay next dose.

In some cases, you may be shown the use of Protamine sulfate, taking into account the following: its efficiency is much lower than described in connection with the overdose unfractionated heparin the ratio benefit/risk of Protamine sulfate should be carefully assessed with regard to its side effects (especially anaphylactic shock).

If you decide to use this treatment, neutralization of a slow in/in a Protamine sulfate.

The effective dose of Protamine sulfate depends on: of the administered dose of heparin (100 antiheparin units of Protamine sulfate can be used to neutralize the activity of 100 IU anti-XA factor activity NMG) the time elapsed after administration of heparin, with a possible reduction of the dose of antidote.

However, to completely neutralize the anti-factor Ha activity is impossible.

Moreover, the kinetics of absorption of low molecular weight heparin can give this neutralization of a temporary nature and require fragmentation of the full calculated dose of Protamine sulfate on multiple injection (2-4), distributed on the day.

Special instructions:

Despite the fact that the concentration of various drugs of low molecular weight heparins expressed in international units of anti-XA factor activity, their effectiveness is not limited to anti-XA factor activity. Replacement dosing one-NMG others is dangerous and unacceptable, because each mode was tested by special clinical trials. Therefore, special caution and compliance with specific instructions for use for each drug.

The risk of bleeding. You must comply with recommended therapeutic regimes (dosing and duration of treatment). Otherwise, you may experience bleeding, especially in patients of risk groups (the elderly, patients suffering from renal insufficiency etc.).

Serious hemorrhage was observed: in elderly patients, in particular in connection with the weakening of renal function with age renal failure in patients weighing less than 40 kg in the case of the duration of treatment, exceeding the recommended (10 days) in case of non-compliance with the recommended conditions of treatment (especially the duration and the establishment of dose based on body weight for the course) in combination with drugs that increase the risk of bleeding.

In any case, needs special control in elderly patients and patients suffering from renal insufficiency and the duration of the drug over 10 days. To detect the accumulation of the drug in some cases it may be useful to measure anti-XA factor activity.

The risk of heparin-induced thrombocytopenia (hit). In the event that a patient receiving treatment LMWH (in coursework or prophylactic doses), observed: the negative dynamics of thrombosis for which the patient is treated, phlebitis, embolism of the pulmonary vessels, the acute limb ischemia, myocardial infarction or stroke, they should be seen as the manifestation of heparin-induced thrombocytopenia (hit), and immediately analyze the number of platelets.

The use in children. Due to lack of data, the use of LMWH in children is not recommended.

The function of the kidneys. Before beginning treatment with LMWH is necessary to monitor renal function, especially in elderly patients over the age of 75 years. Creatinine clearance calculated by the Cockroft formula and based on actual patient body weight: males Cl creatinine = (140-age) ? body weight / (0,814 ? serum creatinine), expressing the age in years, 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.

Detection of severe renal failure (Cl creatinine about 30 ml/min) is a contraindication to use of LMWH in the course form (see “Contraindications”).

Laboratory control

Control the number of platelets

Heparin-induced thrombocytopenia

In connection with danger of development of GIT necessary to control the number of platelets regardless of the indications for use and the dosage. Counting the number of platelets is carried out before the start of treatment or no later than during the first days after the start of treatment and then 2 times a week during the entire course of treatment.

The diagnosis of GIT, it should be assumed, if the number of platelets <100000/mm3 and/or there is a decline in the number of platelets at 30-50% relative to the previous analysis. It develops mostly between 5 and 21 days after starting treatment with heparin (with a maximum frequency of about 10 days).

However, it can occur much earlier in the history of the patient of thrombocytopenia related to heparin treatment, in very rare cases, and after 21 days. The collection of such a history should undergo a systematic interview with the patient before treatment. In addition, the risk of GIT with repeated administration of heparin may persist for several years or even an indefinite time (see “Contraindications”).

In any case, the emergence of GIT is an urgent situation and requires consultation with a specialist. Any significant drop in the number of platelets (30-50% of the original value) should be considered as an alarm to the critical values. In case of a fall in the number of platelets should: immediately check the number of platelets.

To suspend the administration of heparin if the drop is confirmed or identified in this control, in the absence of other obvious causes.

Taking a sample of blood in citrate tube for the study of platelet aggregation in vitro and immunological analysis. However, in such situations, emergency measures do not depend on the results of these analyses, as these analyses are only a few specialized laboratories, and in the best case, the results can be obtained only after several hours. Despite this analysis should be done for precise diagnosis of complications, as with continued treatment with heparin, the risk of thrombosis is very high.

To carry out the prevention and treatment of thrombotic complications of GIT.

If a complication appears, it is necessary to continue anticoagulant treatment, heparin should be replaced by another class of antithrombotic drugs: danaparoid sodium or hirudin-assigned in preventive or therapeutic doses, depending on the situation.

Replacement for vitamin K antagonists can be carried out only after normalization of platelet count, in connection with the risk of increased thrombotic effect.

Replacement of heparin, an antagonist of vitamin K. In this case it is necessary to strengthen clinical and laboratory monitoring to monitor the effects of antagonist of vitamin K.

Because the full effect of the antagonist of vitamin K is not immediately, heparin should continue to enter in equivalent to the dose as needed to achieve the required for this reading level SET in two consecutive tests.

Monitoring of anti-XA factor activity. Since most clinical trials that demonstrated the efficacy of LMWH was performed in the dose set taking into account body weight of the patient and without any special laboratory monitoring, the value of this type of monitoring to assess the effectiveness of LMWH is not installed. However, laboratory control by determining anti-XA factor activity may be beneficial when risk of bleeding in certain clinical situations, often associated with the risk of overdose.

These situations may relate to indications for the course of NMG in connection with the applied doses, at weak and moderate renal insufficiency (Cl calculated by the formula Cockroft, 30-60 ml/min): indeed, in contrast to unfractionated standard heparin, LMWH is mainly excreted by the kidneys, and impaired renal function may lead to a relative overdose. With regard to severe renal failure, it is a contraindication to use of LMWH in exchange mode (see “Contraindications”) at extremes of body weight (underweight or even malnutrition, obesity), with unexplained bleeding.

However, laboratory monitoring is not recommended when using prophylactic doses, LMWH if the treatment is consistent with the recommendations (particularly in relation to duration) and during hemodialysis.

In order to detect possible accumulation after repeated administration is recommended to take blood from the patient with the maximum activity of the drug (in accordance with the available data), i.e.:

approximately 4 hours after the third injection, if the drug is used in the form of two s/C injection per day or approximately 4 hours after the second injection, if the drug is used in the form of a single p/to the injection per day.

Re-determination of anti-XA factor activity to measure the level of heparin in serum — 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 each therapeutic mode generated by anti-XA factor activity.

In accordance with the evidence and according to reports, the average anti-XA factor activity (± standard deviation) observed at the fourth hour after administration of nadroparin dose:

83 IU/kg as two injection per day, 1.01±0,18 IU

168 IU/kg in one injection per day was 1.34±0,15 IU

The average value observed during clinical testing of anti-XA factor activity conducted with the use of chromogenic (amiloliticescoe) method.

Activated partial thromboplastin time (APTT). Some moderately lengthened APTT LMWH. (No clinical significance).

Conducting spinal/epidural anaesthesia in case of preventive use of LMWH. With the use of LMWH and other anticoagulants, during spinal or epidural anesthesia, noted rare cases intraspinal hematoma, leading to prolonged or permanent paralysis.

Risk intraspinal hematoma, appears to be higher when using the epidural catheter than with the use of 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 required (prolonged immobilization, trauma), and the advantages of spinal anesthesia are carefully evaluated, this technique can be applied, the patient received before surgery LMWH injection, if the injection of heparin and use of spinal anesthetic through a period of not less than 12 h In connection with danger of occurrence of hematoma intraspinal careful neurological monitoring.

In almost all cases, preventive treatment LMWH can be initiated 6-8 h after application of the anesthetic or the extraction of the catheter, and neurological control.

Particular caution is required in combination with other drugs that affect hemostasis (namely, NSAIDs, acetylsalicylic acid).

Does not affect the ability to drive and work on the machines.

The use of the system of protection of the needle after the introduction of the drug to use the safety system for syringe Fraxiparina. Hold a used syringe in one hand for the protective housing, with the other hand pull the holder for releasing the latch and moving the cover to protect the needle until it clicks. Used needle fully protected.