Fraxyparin (Fraxiparine)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceNadroparin calciumNadroparin calcium
Dosage form: & nbsphypodermic solution
Composition:

Active substance: calcium supraparin - 9500 ME anti-factor activity in 1 ml.

Excipients: a solution of calcium hydroxide (or dilute hydrochloric acid) is sufficient to pH 5.0 - 7.0, water for injection up to 1.0 ml.

The calcium content of supra -parrin in various forms of release:

Syringes of 0.3 ml - 2850 ME anti-factor activity.

Syringes for 0.4 ml - 3800 ME anti-factor activity.

Syringes of 0.6 ml - 5700 ME anti-factor activity.

Syringes of 0.8 ml - 7600 ME anti-factor activity.

Syringes of 1.0 ml - 9500 ME anti-factor activity.

Description:

Transparent or slightly opalescent, colorless or light yellow solution.

Nadroparin calcium is a low molecular weight heparin (LMWH), obtained by depolymerization from standard heparin. It is a glycosaminoglycan with an average molecular weight of about 4,300 daltons.

Nadroparin shows a high ability to bind to plasma protein antithrombin III (AT III). This binding leads to an accelerated inhibition of factor Xa, which is responsible for the high antithrombotic potential of the supraparin.

Other mechanisms that provide antithrombotic activity of the supraparin include stimulation of the tissue factor pathway inhibitor (TFPI), activation of fibrinolysis by direct release of the tissue plasminogen activator from endothelial cells, and modification of the rheological properties of the blood (decrease in blood viscosity and increase in the permeability of platelet and granulocyte membranes).

Pharmacotherapeutic group:Anticoagulant straight
ATX: & nbsp

B.01   Anticoagulants

Pharmacodynamics:

Nadroparin is characterized by a higher activity with respect to factor Xa, compared with activity against factor IIa. It has both immediate and prolonged antithrombotic activity.

Compared with unfractionated heparin, supraparin has less influence on platelet function and on aggregation and has little effect on primary hemostasis.

In preventive doses does not cause a marked decrease in activated partial thrombin time (APTTV).

At course treatment in the period of maximum activity, the APTT 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.

Pharmacokinetics:

Pharmacokinetic properties are determined on the basis of a change in the anti-Xa factor activity of the plasma.

Absorption. After subcutaneous administration, the maximum anti-Xa activity (Cmax) is achieved in 3-5 hours (Tmax).

Bioavailability. After subcutaneous administration, the supraparin is almost completely absorbed (about 88%). With intravenous administration, the maximum anti-Xa activity is achieved in less than 10 minutes, the half-life (T1/2) is about 2 hours.

Metabolism. Metabolism occurs mainly in the liver (desulphation, depolymerization).

Excretion. The elimination half-life after subcutaneous administration is about 3.5 hours. However, anti-Xa activity persists for at least 18 hours after the injection of supra -parrin at a dose of 1,900 anti-XA ME.


RISK GROUPS

Elderly patients. In elderly patients, in connection with a possible decrease in kidney function, the elimination of supra -parrin can be slowed down. Possible renal failure in this group of patients requires evaluation and appropriate dose adjustment.


Patients with impaired renal function. In clinical studies devoted to the study of pharmacokinetics of supra -parrin in intravenous administration to patients with renal insufficiency of varying severity, a correlation was established between the clearance of supra -parrin and the creatinine clearance. When comparing the values ​​obtained with the indices in healthy volunteers, it was found that AUC and half-life in patients with mild renal insufficiency (CLcr 36-43 ml / min) were elevated to 52 and 39%, respectively, and plasma clearance of supra -parrin was reduced to 63% of normal values. In patients with severe renal failure (CLcr 10-20 ml / min), AUC and half-life were increased to 95% and 112%, respectively, and plasma clearance of supra -parrin was reduced to 50% of normal values. In patients with severe renal dysfunction (CLcr 3-6 ml / min) on hemodialysis, the AUC and the half-life were increased to 62 and 65%, respectively, and the plasma clearance of supra -parrin was reduced to 67% of the normal values.

The results of the study showed that a small accumulation of supra -parrin can be observed in patients with mild or moderate renal insufficiency (creatinine clearance greater than or equal to 30 ml / min and less than 60 ml / min);therefore, the dose of Fraxiparin should be reduced by 25% in such patients receiving Fraxiparin for the treatment of thromboembolism, unstable angina / myocardial infarction without Q wave. Fraksiparin is contraindicated in patients with severe renal failure, in order to treat these conditions.

In patients with mild or moderate renal insufficiency, the use of Fraksiparin for the prevention of thromboembolism, the accumulation of supra-paparin does not exceed that of patients with normal renal function taking treatment doses of Fraksiparin. Therefore, reducing the dose of Frakssiparin taken for prophylactic purposes in this category of patients is not required. In patients with severe renal failure receiving Fraxiparin in prophylactic doses, a dose reduction of 25% is necessary compared with doses given to patients who have normal creatinine clearance.


Hemodialysis. Low molecular weight heparin is injected into the arterial line of the dialysis loops at high enough doses in order to prevent blood coagulation in the loop. Pharmacokinetic parameters do not change in principle, except for overdose,when the passage of the drug into the systemic circulation can lead to an increase in anti-Xa factor activity associated with the final phase of renal failure.

Indications:

Prevention of thromboembolic complications:

  • at general surgical and orthopedic interventions;
  • in patients with a high risk of thrombosis (in acute respiratory and / or heart failure) in an intensive care unit.

Treatment of thromboembolism.

Prevention of coagulation during hemodialysis.

Treatment of unstable angina and myocardial infarction without a Q wave.

Contraindications:

- Hypersensitivity to nadroparin or any other component of the drug;

- Thrombocytopenia in the application of nadroparin in the anamnesis;

- Signs of bleeding or an increased risk of bleeding due to hemostasis disorder, with the exception of DIC syndrome not caused by heparin;

- Organic damage to organs with a tendency to bleeding (eg, acute ulcer of the stomach or duodenum);

- Trauma or surgery on the brain and spinal cord or on the eyes;

- Intracranial hemorrhage;

- Acute septic endocarditis;

- Severe renal insufficiency (creatinine clearance less than 30 ml / min) in patients receiving Fraxiparin for the treatment of thromboembolism, unstable angina and myocardial infarction without Q wave;

- Children's age (<18 years).

Carefully:

Caution should be given to Fraksiparin in the following situations, due to an increased risk of bleeding:

- With hepatic insufficiency;

- With renal insufficiency;

- With severe arterial hypertension;

- With peptic ulcers in a history or other diseases with an increased risk of bleeding;

- In case of circulatory disorders in the choroid and retina of the eye;

- In the postoperative period after operations on the brain and spinal cord or on the eyes;

- Patients weighing less than 40 kg;

- In case of treatment duration exceeding recommended (10 days);

- In case of non-observance of the recommended treatment conditions (in particular, duration and establishment of a dose based on body weight for the course application);

- When combined with drugs that increase the risk of bleeding (see section "Interactions with other drugs").

Pregnancy and lactation:

Pregnancy

Experiments on animals did not show teratogenic or fetotoxic effects of nadroparin, however, at the present time there are only limited data concerning the penetration of perioraparin through the placenta in humans. Therefore, the use of Fraksiparin during pregnancy is not recommended, except when the potential benefit to the mother exceeds the risk to the fetus.

Lactation

At present, there are only limited data on the release of pereraparin in breast milk. In this regard, the use of nadroparin during breastfeeding is not recommended.

Dosing and Administration:

The technique of subcutaneous injection

Preferably, in the patient's position lie in the subcutaneous tissue of the anterolateral or posterolateral surface of the abdominal region, alternately from the right and left sides. Admission to the hip is permissible.

To avoid loss of the drug when using syringes, do not remove air bubbles before injection.

The needle should be inserted perpendicularly, and not at an angle, into a pinched skin fold, which must be kept between the thumb and index finger until the end of the solution.Do not rub the injection site after injection.

Prevention of thromboembolism

general surgery

The recommended dose of Fraksiparin is 0.3 ml (2850 anti-XA ME) subcutaneously, 2-4 hours before the operation, then Fraksiparin is administered 1 time per day. Treatment is continued for at least 7 days and during the period of risk of thrombosis, before transferring the patient to an outpatient schedule.

Orthopedic surgery

Fraxyparin is administered subcutaneously, the dosage depends on the body weight of the patient, and is listed below in the table, at the rate of 38 anti-Ha IU / kg weight, which can be increased to 50% on the 4th postoperative day. The initial dose is prescribed 12 hours before the operation, the second dose - 12 hours after the end of the operation. Further, Frakssiparin continues to be applied 1 time per day during the period of risk of thrombosis before transferring the patient to an outpatient schedule. The minimum duration of therapy is 10 days.

Body weight of the patient (kg)

The dose of Fraxiparin administered 12 hours before and after 12 hours

after the operation, then 1 time per day until the 3rd day after the operation

The dose of Fraksiparin, administered once a day, starting from the 4th day after the operation

Volume, ml

Anti-Xa ME

Volume, ml

Anti-Xa ME

<50

0,2

1900

0,3

2850

50-69

0,3

2850

0,4

3800

>70

0,4

3800

0,6

5700

Patients with a high risk of thrombosis, usually in intensive care units (respiratory failure and / or respiratory tract infection and / or heart failure)

Frakssiparin is administered subcutaneously, once a day. The dose depends on the body weight of the patient and is indicated below in the table. Frakssiparin is used during the entire period of risk of thrombosis.

Body weight of the patient (kg)

The dose of Fraksiparin administered once a day

Fractsparin volume, ml

Anti-Xa ME



<70

0,4

3800

More than 70

0,6

5700

Treatment of unstable angina and myocardial infarction without a Q wave

Fraksiparin is administered subcutaneously 2 times a day (every 12 hours). Duration of treatment is usually 6 days. In clinical studies, patients with unstable angina pectoris / myocardial infarction without a Q wave Fraksiparin was administered in combination with aspirin, at a dose of 325 mg per day.

The initial dose used as a single intravenous bolus injection and subsequent doses is administered subcutaneously. The dose depends on the patient's body weight and is listed below in the table, based on 86 anti-Ha IU / kg body weight.

Body weight of the patient (kg)

Initial dose, for intravenous administration (bolus)

Subcutaneous injection (every 12 hours)

Anti-Xa ME

<50

0.4 ml

0.4 ml

3800

50-59

0.5 ml

0.5 ml

4750

60-69

0.6 ml

0.6 ml

5700

70-79

0.7 ml

0.7 ml

6650

80-89

0.8 ml

0.8 ml

7600

90-99

0.9 ml

0.9, ml

8550

> 100

1.0ml

1.0 ml

9500

Treatment of thromboembolism

In the treatment of thromboembolism, oral anticoagulant therapy, in the absence of contraindications, should be initiated as early as possible. Therapy Frakssparinom should not be discontinued until the target values ​​of the prothrombin time.

Fraksiparin is administered subcutaneously 2 times a day (every 12 hours), the usual course duration is 10 days. The dose depends on the patient's body weight and is listed below in the table, based on 86 anti-Ha IU / kg body weight.

Body weight of the patient (kg)

Twice a day, duration 10 days

Volume (ml)

Anti-Xa ME

<50

0.4

3800

50-59

0.5

4750

60-69

0.6

5700

70-79

0.7

6650

80-89

0.8

7600

>90

0.9

8550

Prevention of blood clotting in the system of extracorporeal circulation in hemodialysis

The dose of Fraksiparin should be set for each patient individually, taking into account the technical conditions of dialysis.

Fraksiparin is injected once into the arterial line of the dialysis loop at the beginning of each session. For patients who do not have an increased risk of bleeding, the following initial doses are recommended, depending on body weight,sufficient for a 4-hour dialysis session:

Body weight of the patient (kg)

Injection into the arterial line of the dialysis loop at the beginning of the dialysis session.

Volume (ml)

Anti-Xa ME

<50

0.3

2850

50-69

0.4

3800

>70

0.6

5700

In patients with an increased risk of bleeding, dialysis sessions can be performed using a half dose of the drug.

In the event that the dialysis session lasts longer than 4 hours, additional small doses of Fraksiparin may be administered.

When carrying out subsequent dialysis sessions, the dose should be selected depending on the observed effects. It is necessary to observe the patient during the dialysis procedure due to possible bleeding or signs of thrombus formation in the dialysis system.

Elderly patients

In elderly patients, dose adjustments are not required, except for patients with impaired renal function. Before starting treatment with Fraksiparin, it is recommended that the kidney function be assessed.

Renal insufficiency

Prevention of thromboembolism

In patients with mild and moderate renal failure (creatinine clearance> 30 ml / min and less than 60 ml / min), a dose reduction is not required if Fraxiparin is used to prevent thrombosis.In patients with severe renal failure (creatinine clearance less than 30 ml / min), the dose should be reduced by 25%. In patients with severe renal failure (creatinine clearance less than 30 ml / min), the dose should be reduced by 25%.

Treatment of thromboembolism, prevention of thromboembolism in patients with a high risk of thrombosis (unstable angina and myocardial infarction without a Q wave)

In patients with mild and moderate renal failure receiving Fraxiparin for the treatment of these diseases, the dose should be reduced by 25%. Fraksiparin is contraindicated in patients with severe renal insufficiency.

Patients with impaired hepatic function

There were no special studies for this group of patients.

Side effects:

The following classification of unwanted reactions is used depending on the frequency of occurrence: very often (> 1/10), often (> 1/100, <1/10), sometimes (> 1/1000, <1/100), rarely (> 1 / 10,000, <1/1000), very rarely (<1 / 10,000).

From the blood and lymphatic system: very often - bleeding is different to localization, more often in patients with other risk factors; rarely - thrombocytopenia; very rarely - eosinophilia, reversible after discontinuation of the drug.

From the immune system: very rarely - hypersensitivity reactions (including Quincke's edema and skin reactions).

From the side of metabolism: very rarely - reversible hyperkalemia associated with the ability of heparins to inhibit the secretion of aldosterone, especially in patients with a risk group.

Hepatobiliary disorders: often - an increase in the level of hepatic transaminases, which is usually transient in nature.

From the skin and subcutaneous tissues: very often - the formation of a small subcutaneous hematoma at the injection site. In some cases there is the appearance of dense nodules that do not signify the encapsulation of heparin, which disappear after a few days. Very rarely - necrosis of the skin, usually at the injection site. Necrosis is usually preceded by purpura or an infiltrated or painful erythematous spot that may or may not be accompanied by common symptoms. In such cases, treatment with Fraksiparin should be stopped immediately.

On the part of the reproductive system: very rarely - priapism.

Overdose:

Symptoms

The main sign of an overdose with subcutaneous or intravenous administration is bleeding.It is necessary to monitor the number of platelets and other parameters of the blood coagulation system. Minor bleeding does not require special therapy, it is usually sufficient to reduce or delay the subsequent dose of Fraksiparin.


Treatment

The use of protamine sulfate is necessary only in severe cases. Protamine sulfate has a pronounced neutralizing effect with respect to anticoagulant effects of heparin, however some anti-Xa activities can be restored.

0.6 ml of protamine sulfate neutralizes about 950 anti-Xa ME supraparin. The dose of protamine sulfate is calculated taking into account the time elapsed after the administration of heparin, with a possible reduction in the dose of the antidote.

Interaction:

The development of hyperkalemia may depend on the simultaneous presence of several risk factors. Medications that cause hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers II, non-steroidal anti-inflammatory drugs, heparins (low molecular or unfractionated), ciclosporin and tacrolimus, trimethoprim. The risk of developing hyperkalemia increases with the combination of the above-mentioned agents with FRAXIPARIN.

Joint use of Frakssiparin with drugs that affect hemostasis, such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), vitamin K antagonists, fibrinolytics and dextran, leads to a mutual enhancement of the effect.

In addition, it should be taken into account: platelet aggregation inhibitors (except for acetylsalicylic acid as an analgesic and antipyretic drug, ie, in a dose exceeding 500 mg, NSAIDs): abciximab, acetylsalicylic acid in antiplatelet doses (50-300 mg) with cardiological and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban, the risk of bleeding increases.

Fraxyparin should be administered with caution to patients receiving oral anticoagulants, systemic glucocorticosteroids and dextrans. When administering oral anticoagulants to patients receiving Fraksiparin, its use should continue until the prothrombin time has stabilized to the desired value.

Special instructions:

Particular attention should be given to specific instructions for use for each drug, belonging to the class of low molecular weight heparins, various dosage units (ED or mg) can be used in them. As a consequence, the alternation of Fraksiparin with other LMWH in long-term treatment is not permissible. Also it is necessary to pay attention to what kind of drug is used - Fraksiparin or Fraksiparin Forte, tk. this affects the dosing regimen. Graduated syringes are designed to adjust the dose depending on the weight of the patient's body.

Frakssiparin is not intended for intramuscular administration.

In the treatment of Fraxiparin, a clinical monitoring of the measurement of the number of platelets


Thrombocytopenia

Since the use of heparins, there is the possibility of developing thrombocytopenia (heparin-induced thrombocytopenia), during the whole course of treatment with Fraxiparin, it is necessary to monitor the level of platelets.

There have been reports of rare cases of thrombocytopenia, sometimes severe, that could be associated with arterial or venous thrombosis, which is important to consider in the following cases:

-in thrombocytopenia;

-with a significant decrease in platelet count (by 30-50% compared with normal indices);

- with negative dynamics from the thrombosis side, about which the patient is receiving treatment;

-In DIC-syndrome.

In these cases, treatment with Fraksiparin should be discontinued.

These effects are of an immunoallergic nature and usually occur between the 5th and 21st days of treatment, but may occur even earlier if the patient has heparin-induced thrombocytopenia in the anamnesis.

In the presence of heparin-induced thrombocytopenia in the history (against the background of usual or low-molecular heparins), treatment with Fraksiparin can be prescribed if necessary. However, in this situation, strict clinical monitoring and, at a minimum, a daily measurement of the number of platelets are shown. If thrombocytopenia occurs, the use of Fraksiparin should be stopped immediately.

If thrombocytopenia occurs against the background of heparins (normal or low molecular weight), then the use of anticoagulants of other groups should be considered. If other drugs are not available, then another low molecular weight heparin may be used.It should be observed daily the number of platelets in the blood. If signs of an initial thrombocytopenia continue to be observed after the drug has been changed, treatment should be stopped as soon as possible.

It should be remembered that the control of platelet aggregation, based on in vitro tests, is of limited importance in the diagnosis of heparin-induced thrombocytopenia.


Elderly patients

Before the beginning of treatment with Frakssparinum it is necessary to estimate or appreciate function of kidneys.


Hyperkalemia

Heparins can inhibit the secretion of aldosterone, which can lead to hyperkalemia, especially in patients with elevated potassium in the blood or in patients at risk of increasing potassium in the blood, for example, patients with diabetes mellitus, chronic renal failure, metabolic acidosis or patients taking drugs, which can cause hyperkalemia. The risk of hyperkalemia increases with prolonged therapy, but is usually reversible upon cancellation. In patients at risk, the level of potassium in the blood should be monitored.


Spinal / epidural anesthesia / spinal puncture and concomitant medications

The risk of spinal / epidural hematomas increases in persons with established epidural catheters or concomitant use of other drugs that may affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or other anticoagulants. The risk, apparently, also increases with traumatic or repeated epidural or spinal punctures. Thus, the question of the combined use of neuraxial blockade and anticoagulants should be addressed individually after assessing the efficacy / risk ratio in the following situations:

- in patients who are already receiving anticoagulants, the need for spinal or epidural anesthesia should be justified;

- in patients who are planning an elective surgical intervention with spinal or epidural anesthesia, the need to introduce anticoagulants should be justified.

If a patient undergoes lumbar puncture or spinal or epidural anesthesia, a sufficient time interval between the administration of Fraksiparin and the introduction or removal of a spinal / epidural catheter or needle should be observed.

Careful observation of the patient is necessary in order to identify signs and symptoms of neurological disorders. If violations are found in the neurological status of the patient, urgent appropriate therapy is required.


Salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), and platelet aggregation inhibitors

In the prevention or treatment of venous thromboembolism, as well as in the prevention of blood clotting in the extracorporeal circulation system in hemodialysis, the combined use of Fraksiparin with preparations such as acetylsalicylic acid, other salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), and platelet aggregation inhibitors, this may increase the risk of bleeding.

Effect on the ability to drive transp. cf. and fur:

There is no evidence of the effect of Fraksiparin on the ability to drive a car / machinery.

Form release / dosage:

Solution for subcutaneous administration, 9500 ME anti-Xa / ml.

Packaging:

For 0.3 ml, 0.4 ml, 0.6 ml, 0.8 ml or 1.0 ml of the drug in a single-dose glass syringe with a protective casing, a tip with a stainless steel needle, a closed cap.

2 syringes are packed in a transparent blister of PVC / PE film.

For 1 or 5 blisters (2 or 10 syringes), together with the instructions for use are placed in a cardboard box.

Storage conditions:

List B.

Store at a temperature not exceeding 30 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription
Registration number:П N015872 / 01
Date of registration:18.06.2009
The owner of the registration certificate:Aspen Pharma Trading LimitedAspen Pharma Trading Limited
Manufacturer: & nbsp
Representation: & nbspAspen Hells Ltd.Aspen Hells Ltd.
Information update date: & nbsp04.02.2015
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