Fraxiparine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FRAXIPARINE® (FRAXIPARINE™)

Composition:

Active substance: nadroparin calcium;

1 ml of solution contains 9500 IU anti-Xa of nadroparin calcium;

1 pre-filled syringe (0.6 ml) contains 5700 IU anti-Xa of nadroparin calcium;

1 pre-filled syringe (0.8 ml) contains 7600 IU anti-Xa of nadroparin calcium;

Excipients: calcium hydroxide solution (or diluted hydrochloric acid), water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear or slightly opalescent, colorless or light yellow solution – at the time of release;

• clear or slightly opalescent, colorless or light yellow or slightly brownish or slightly dark yellow solution – at the end of shelf life.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01AB06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Nadroparin is a low-molecular-weight heparin (LMWH) in which the antithrombotic activity is dissociated from the anticoagulant activity of standard heparins. It has higher anti-Xa activity than anti-IIa or antithrombin activity. The ratio of these types of activity for nadroparin ranges from 2.5 to 4.

Pharmacodynamic effects

At prophylactic doses, nadroparin does not significantly affect activated partial thromboplastin time (APTT). At therapeutic doses and during the period of maximum nadroparin activity, APTT may increase by 1.4 times compared to the initial value. This increase reflects the residual antithrombotic effect of nadroparin.

Pharmacokinetics.

Pharmacokinetic properties are determined by measuring plasma anti-Xa factor activity.

Availability

After subcutaneous injection, nadroparin is rapidly and almost 100% absorbed; maximum plasma activity levels are reached within 3–4 hours when nadroparin is administered twice daily. When nadroparin is administered once daily, this peak occurs 4–6 hours after injection.

Metabolism

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

Distribution

After subcutaneous administration, the half-life of anti-Xa activity of LMWH is longer than that of unfractionated heparins and amounts to 3–4 hours.

When low-molecular-weight heparins are administered, anti-IIa activity in blood plasma decreases more rapidly than anti-Xa activity.

Elimination

Nadroparin is primarily excreted unchanged or minimally changed via the kidneys.

Special patient groups

Elderly patients

As renal physiological function declines with age, drug elimination is slowed. This does not require dose adjustment or changes in dosing frequency when the drug is used for prophylactic purposes, provided renal function remains within acceptable limits, i.e., only slightly impaired.

Before administering LMWH to elderly patients (over 75 years of age), a systematic assessment of renal function should be performed using the Cockcroft formula (see section "Special precautions for use").

Renal impairment

In a pharmacokinetic study in which 5 patients with moderate renal impairment, 7 patients with severe renal impairment, and 7 patients on hemodialysis received a single intravenous dose of nadroparin, a correlation was demonstrated between nadroparin clearance and creatinine clearance. In patients with moderate renal impairment (creatinine clearance 36–43 mL/min), mean area under the concentration-time curve (AUC) and elimination half-life increased by 52% and 39%, respectively, compared to healthy volunteers. In these patients, mean plasma clearance of nadroparin decreased to 63% of normal. Wide individual variability was observed in this study. In patients with severe renal impairment (creatinine clearance 10–20 mL/min), mean AUC and half-life increased by 95% and 112%, respectively, compared to healthy volunteers. Plasma clearance in patients with severe renal impairment decreased by 50% compared to patients with normal renal function.

Hemodialysis

Low-molecular-weight heparin is administered into the arterial line of the dialysis circuit at doses sufficient to prevent blood clotting in the circuit.

Between two hemodialysis sessions in patients with severe renal impairment (creatinine clearance 3–6 mL/min) undergoing hemodialysis, mean AUC and elimination half-life increased by 62% and 65%, respectively, compared to healthy volunteers. Plasma clearance in patients with severe renal impairment undergoing hemodialysis was reduced by 67% compared to patients with normal renal function (see sections "Special precautions for use" and "Method of administration and dosage").

In cases of overdose, nadroparin entry into systemic circulation may lead to increased anti-Xa activity, which is associated with end-stage renal failure.

Clinical characteristics.

Indications.

Prevention of thromboembolic complications, namely:

• venous thromboembolic disease in surgical procedures associated with moderate and high risk of complications;
• in patients with acute illnesses (such as acute heart failure, respiratory failure, severe infections or rheumatic diseases) and reduced mobility who are at high risk of developing thromboembolic complications.

Prevention of blood coagulation in the extracorporeal circulation circuit during hemodialysis (sessions usually lasting ≤ 4 hours).

Treatment of deep vein thrombosis.

Treatment of unstable angina and myocardial infarction without pathological Q-wave on ECG.

Contraindications.

Hypersensitivity to nadroparin or to any other component of the medicinal product, or to heparin or its derivatives, including other low-molecular-weight heparins.

History of severe heparin-induced thrombocytopenia (HIT) type II caused by unfractionated or low-molecular-weight heparin, or any other thrombocytopenia induced by the use of nadroparin (see section "Special precautions for use").

Signs of bleeding or increased risk of bleeding related to coagulation disorders, except for disseminated intravascular coagulation (DIC) not caused by heparin (see section "Special precautions for use").

Organic lesions with tendency to bleeding (e.g. acute peptic ulcer of the stomach or duodenum).

Hemorrhagic stroke.

Acute infective endocarditis (except for certain emboligenic cardiopathies).

Diabetic or hemorrhagic retinopathy.

In the absence of data, in severe renal impairment (creatinine clearance less than 30 mL/min according to the Cockcroft formula) for treatment with therapeutic doses of deep vein thrombosis, thromboembolism, unstable angina and myocardial infarction without pathological Q-wave on ECG, except when used during hemodialysis.

The use of epidural or spinal anesthetics is contraindicated during treatment with LMWH.

Nadroparin in therapeutic doses is not recommended in the following situations:

• extensive ischemic stroke in the acute phase, with or without impaired consciousness; in case of embolic stroke, nadroparin should not be administered earlier than 72 hours after the stroke; the efficacy of therapeutic-dose LMWH has not been established regardless of the cause, duration, or severity of stroke;
• it is not recommended to administer the medicinal product to patients with mild or moderate renal function impairment. If nadroparin use is necessary in such patients, the following should be considered:

− if, in the physician’s opinion, dose reduction of nadroparin is appropriate due to individual risk factors for bleeding and thromboembolic complications in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min and < 50 mL/min), the dose should be reduced by 25–33% (see sections "Pharmacokinetics", "Special precautions for use" and "Dosage and administration");

− dose reduction of nadroparin is not required in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min) (see section "Dosage and administration").

Nadroparin in therapeutic doses is also not recommended for patients of any age in combination with the following medicinal products (see section "Interaction with other medicinal products and other forms of interaction"):

• acetylsalicylic acid at doses used for analgesia, antipyresis, and anti-inflammatory purposes;
• nonsteroidal anti-inflammatory drugs (NSAIDs) (systemic administration);
• dextran 40 (parenteral administration).

Nadroparin in prophylactic doses is not recommended in the following situations:

• severe renal impairment (creatinine clearance approximately 30 mL/min according to the Cockcroft formula). However, if, in the physician’s opinion, dose reduction of nadroparin is appropriate due to individual risk factors for bleeding and thromboembolic complications, the dose should be reduced by 25–33% (see sections "Pharmacokinetics", "Special precautions for use" and "Dosage and administration");
• intracranial hemorrhage – within the first 24 hours.

Nadroparin in prophylactic doses is also not recommended for patients over 65 years of age in combination with the following medicinal products (see section "Interaction with other medicinal products and other forms of interaction"):

• acetylsalicylic acid at doses used for analgesia, antipyresis, and anti-inflammatory purposes;
• nonsteroidal anti-inflammatory drugs (NSAIDs) (systemic administration);
• dextran 40 (parenteral administration).

Nadroparin in prophylactic doses is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min according to the Cockcroft formula).

Interaction with other medicinal products and other forms of interaction.

The use of certain medicinal products and drug classes increases the risk of developing hyperkalemia. These include potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins (low-molecular-weight or unfractionated), cyclosporine and tacrolimus, trimethoprim.

The development of hyperkalemia may depend on several concomitant risk factors.

The risk of hyperkalemia increases when nadroparin is combined with the medicinal products listed above.

Combinations not recommended

The use of therapeutic-dose LMWH in patients under 65 years of age and the use of LMWH at any dose in patients over 65 years of age with acetylsalicylic acid at doses used for analgesia (as well as with other salicylates), anti-inflammatory agents (NSAIDs and systemic glucocorticoids), and antiplatelet agents (abciximab, acetylsalicylic acid at doses used for anticoagulation in cardiological and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban) is not recommended.

Concomitant use of nadroparin with these medicinal products increases the risk of bleeding, as salicylates and NSAIDs inhibit platelet activity and adversely affect the gastric and duodenal mucosa.

In such cases, analgesics and antipyretics not containing salicylates (e.g. paracetamol) should be used.

In clinical trials for the treatment of unstable angina and myocardial infarction without pathological Q-wave, nadroparin was administered concomitantly with aspirin at doses not exceeding 325 mg per day (see sections "Special precautions for use" and "Dosage and administration").

If concomitant use of nadroparin and NSAIDs is necessary, careful clinical monitoring should be ensured.

Dextran 40 (for parenteral use): concomitant use of nadroparin and dextran 40 increases the risk of bleeding, as dextran 40 inhibits platelet activity.

Combinations to be used with caution

Oral anticoagulants: nadroparin should be prescribed with caution to patients receiving oral anticoagulants, as this combination leads to mutual potentiation of effect.

When replacing nadroparin with an oral anticoagulant, intensified clinical monitoring is required, and nadroparin administration should be continued as long as necessary to achieve stabilization of the international normalized ratio (INR) at the target value.

Combinations with warnings

Concomitant use of nadroparin with medicinal products affecting hemostasis at different levels increases the risk of bleeding. Therefore, careful clinical and laboratory monitoring is required when prophylactic doses of LMWH are used concomitantly in patients of any age with oral anticoagulants, antiplatelet agents (abciximab, NSAIDs, acetylsalicylic acid at any dose, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban), and thrombolytics.

Special precautions for use.

Cross-reactivity

Cross-reactivity between unfractionated heparins and LMWHs is well documented. Delayed hypersensitivity reactions have been reported in patients with cross-reactivity between unfractionated heparins and LMWHs.

Prior to initiating treatment with LMWH, a careful assessment of previous hypersensitivity reactions to unfractionated heparin should be performed.

Although concentrations of various low-molecular-weight heparin (LMWH) preparations are expressed in anti-Xa international units, their efficacy is not solely limited to anti-Xa activity. Therefore, it is dangerous to substitute one LMWH for another LMWH or another type of synthetic polysaccharide using the same dosing regimen, as each of these medicinal products has a specific dosing schedule validated in dedicated clinical trials. Thus, particular attention should be paid to the specific instructions for use of each medicinal product.

Bleeding risk

The recommended treatment regimen (dosing schedule and duration of therapy) must be strictly followed. Otherwise, bleeding may occur, especially in patients with risk factors (elderly patients, patients with renal impairment, etc.).

In particular, severe bleeding during nadroparin use has been observed in the following patient groups:

• elderly patients — particularly due to age-related decline in renal function;
• patients with renal impairment;
• patients with body weight less than 40 kg;
• in case of exceeding the recommended duration of treatment (10 days);
• in case of non-compliance with recommended treatment conditions (especially duration of treatment and weight-adjusted therapeutic doses);
• when used concomitantly with medicinal products that increase bleeding risk (see section "Interaction with other medicinal products and other forms of interaction").

Careful monitoring of patients is required when nadroparin is administered to elderly patients and/or patients with renal impairment, as well as when the recommended duration of treatment (10 days) is exceeded.

Anti-Xa activity may be used in certain cases to detect drug accumulation (see section "Monitoring of laboratory parameters" below).

Risk of heparin-induced thrombocytopenia (HIT)

Due to the risk of heparin-induced thrombocytopenia, platelet counts should be monitored throughout the entire course of treatment with Fraxiparine®.

Isolated cases of thrombocytopenia, sometimes severe, have been reported and may be associated with arterial or venous thrombosis. This should be particularly considered in the following situations: thrombocytopenia, any significant decrease in platelet count (by 30% to 50% compared to baseline or to a level <150,000/mm³ or 150×10⁹/L), lack of improvement in thrombosis for which treatment was initiated, development of thrombosis during treatment (phlebitis, pulmonary embolism, acute lower limb ischemia, myocardial infarction, or ischemic stroke), or disseminated intravascular coagulation syndrome. In such cases, the possibility of HIT should be considered and platelet count should be checked immediately. If these events occur, treatment with Fraxiparine® should be discontinued.

Use in children

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

Renal function

Nadroparin is primarily eliminated via the kidneys, resulting in increased exposure in patients with renal impairment (see section "Pharmacokinetics"). These patients are at increased risk of bleeding; therefore, nadroparin therapy should be used with caution.

For patients with creatinine clearance ≥30 mL/min and <50 mL/min, the physician may consider a reduced dose of nadroparin based on individual bleeding risk versus thromboembolic risk for the specific patient (see section "Method of administration and dosage").

Renal function should be assessed prior to initiating LMWH therapy, especially in elderly patients (over 75 years), by calculating creatinine clearance (CrCl) using the Cockcroft-Gault formula with the patient's most recent body weight:

for men: CrCl = (140 – age) × body weight / (0.814 × serum creatinine concentration); age in years, body weight in kilograms, serum creatinine concentration in µmol/L.

For women, the result should be adjusted by multiplying by 0.85. To convert serum creatinine concentration to mg/dL, multiply the result by 8.8.

The use of the drug at therapeutic doses is contraindicated in severe renal impairment (creatinine clearance approximately 30 mL/min) (see section "Contraindications").

Monitoring of laboratory parameters

Monitoring platelet counts in patients receiving LMWH who are at risk of developing heparin-induced thrombocytopenia (HIT) (or HIT type II)

To detect HIT early during therapy, patient monitoring should be performed as follows:

• After surgery or trauma (within the last 3 months): regular biological monitoring is required when nadroparin is used for treatment or prophylaxis, as the incidence of HIT in these patients is >0.1% and even >1%. Platelet counts should be determined:
  • before initiation of LMWH therapy or within the first 24 hours after starting therapy;
  • twice weekly during the first month of therapy (period of highest risk);
  • once weekly throughout the treatment period if long-term therapy is required.
• In the absence of surgery or trauma (within the last 3 months): regular biological monitoring (see previous section) is required when nadroparin is used for treatment or prophylaxis in the following cases:
  • history of treatment with unfractionated heparin (UFH) or LMWH within the last 6 months, as the incidence of HIT in these patients is >0.1% and even >1%;
  • presence of underlying conditions associated with potential risk of HIT.

In other cases, due to the low incidence of HIT (<0.1%), platelet counts should be determined:

• before initiation of LMWH therapy or within the first 24 hours after starting therapy;
• if specific clinical signs of HIT occur (arterial or venous thromboembolism, any painful skin lesions at the injection site, any signs of allergy or anaphylactoid reactions during therapy). Patients should be informed about the possible occurrence of such clinical signs and the need to contact their physician if they appear.

HIT should be suspected if platelet count decreases to <150,000/mm³ (150×10⁹/L) or by 30–50% compared to baseline.

No dose adjustment of nadroparin is required in patients with mild renal impairment (creatinine clearance ≥50 mL/min) (see section "Method of administration and dosage").

The above-mentioned effects have an immune-allergic nature and usually occur between the 5th and 21st day of treatment (most commonly on day 10), but may occur earlier in patients with a history of heparin-induced thrombocytopenia. Cases of HIT have also been reported after 21 days of therapy.

If there is a history of thrombocytopenia (except for HIT type I, see section "Contraindications") occurring during heparin treatment (both standard and low-molecular-weight), Fraxiparine® may be prescribed if necessary. In such cases, careful clinical monitoring and daily platelet count determination are required. If thrombocytopenia occurs, treatment with Fraxiparine® should be discontinued immediately.

If thrombocytopenia occurred during heparin treatment (both standard and low-molecular-weight), consider the possibility of using antithrombotic agents from another class. If such a drug is not available, substitution with another low-molecular-weight heparin may be considered if heparin use is essential. In such cases, platelet counts should be checked at least once daily, and treatment should be discontinued as early as possible, as cases of persistent thrombocytopenia after switching products have been described (see section "Contraindications").

Prior to initiating therapy, possible history of thrombocytopenia during heparin use should be established.

In all cases, HIT is an emergency condition requiring specialist intervention.

Any significant decrease in platelet count (by 30–50% from baseline) requires immediate attention before the count reaches a critical level. In case of decreased platelet count, the following steps should be taken:

1. immediately determine platelet count;
2. discontinue heparin therapy, if the decrease in platelet count is confirmed and progressing, according to test results, and no other obvious causes are present.

A blood sample must be placed in a citrate tube for in vitro platelet aggregation studies and immunological assays. However, immediate action should be taken before test results are available, as these in vitro platelet aggregation and immunological tests are performed only in a few specialized laboratories and results may not be available for several hours. Nevertheless, such tests must be performed to establish a definitive diagnosis, as continuing heparin therapy carries a high risk of thrombosis;

1. prevent or treat thrombotic complications of HIT.

If further anticoagulant therapy is required, heparin must be replaced with an anticoagulant from another class — danaparoid sodium or lepirudin — at prophylactic or therapeutic doses depending on the clinical situation.

If heparin is replaced with a vitamin K antagonist (VKA), the latter should only be initiated after platelet count normalization; otherwise, there is a risk of worsening thrombotic effect.

Replacing heparin with vitamin K antagonists

Careful clinical and laboratory monitoring (prothrombin time by Quick method and international normalized ratio) is required to monitor the effect of VKA.

Since the full effect of VKA takes time to develop, heparin administration should be continued at an equivalent dose for as long as necessary to achieve a target INR range confirmed by two consecutive tests.

Monitoring anti-Xa activity

Most clinical trials confirming the efficacy of LMWH were conducted using weight-adjusted dosing without specific laboratory monitoring, and the usefulness of such monitoring for assessing LMWH efficacy has not been established. However, laboratory monitoring based on anti-Xa activity may be useful for controlling bleeding risk in certain clinical situations, often associated with overdose risk.

These situations include therapeutic-dose LMWH use in the following cases:

• mild to moderate renal impairment (creatinine clearance 30–60 mL/min by Cockcroft formula): unlike unfractionated heparin, LMWH is primarily eliminated via the kidneys, and renal impairment may lead to relative overdose; severe renal impairment is a contraindication for therapeutic-dose LMWH use (see section "Contraindications");
• underweight or overweight (low body weight or even cachexia, obesity);
• unexplained bleeding.

Conversely, laboratory monitoring is not recommended when prophylactic doses are used, provided LMWH treatment follows established recommendations (especially regarding duration of therapy) and during hemodialysis.

To detect possible drug accumulation after repeated administration, blood samples should be obtained at times of peak drug activity (based on available data), i.e.:

• approximately 4 hours after the 3rd injection, if the drug is administered as subcutaneous injections twice daily;
• approximately 4 hours after the 2nd injection, if the drug is administered as a single daily subcutaneous injection.

Depending on previous test results, repeat determination of anti-Xa activity (e.g., every 2 or 3 days) and dose adjustment of LMWH should be considered.

Each LMWH and each dosing regimen provides different levels of anti-Xa activity.

Approximate mean anti-Xa activity values (± standard deviation) observed 4 hours after nadroparin injection are as follows:

• with a dose of 83 IU/kg administered twice daily — 1.01 ± 0.18 IU;
• with a dose of 166 IU/kg administered once daily — 1.34 ± 0.15 IU.

These mean values were obtained in clinical trials using chromogenic (amidolytic) methods for anti-Xa activity determination.

Activated partial thromboplastin time (aPTT)

Some LMWHs may cause a moderate increase in aPTT. Since this effect lacks clinical significance, any monitoring based on this test is ineffective.

Situations associated with risk

Nadroparin should be used with caution in situations associated with increased risk of bleeding, such as:

• hepatic insufficiency;
• severe arterial hypertension;
• gastric or duodenal ulcer or other organic lesions with a history of bleeding risk;
• vascular diseases of the choroid and retina;
• period after surgery on the brain or spinal cord, or on the eyes;
• hyperkalemia;
• risk of intraspinal bleeding should be considered when performing lumbar puncture. If possible, lumbar puncture should be postponed.

Heparin may suppress aldosterone secretion and cause hyperkalemia, particularly in patients with elevated plasma potassium levels or those with risk factors (diabetes mellitus, chronic renal failure, metabolic acidosis, or use of other drugs that may cause hyperkalemia [e.g., angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs]).

The risk of hyperkalemia increases with longer treatment duration but is usually reversible. Plasma potassium levels should be monitored in patients with risk factors during prolonged treatment.

Spinal/epidural anesthesia during prophylactic use of LMWH

Rare cases of intraspinal hematoma leading to permanent or persistent paralysis have been reported with LMWH use, as with other anticoagulants, during spinal or epidural anesthesia.

The risk of spinal/epidural hematomas increases with the use of an epidural catheter or concomitant use of other drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors, or other anticoagulants. The risk is also increased with repeated or failed spinal puncture; therefore, the decision to combine neuraxial blockade with anticoagulants should be made after careful assessment of benefit-risk ratio in each individual case:

• for patients receiving anticoagulants, the necessity of spinal or epidural anesthesia should be justified;
• for patients requiring anesthesia during surgery, the necessity of anticoagulant use should be justified.

If preoperative LMWH treatment is necessary (due to prolonged immobilization, trauma) and a careful benefit-risk assessment of spinal or epidural anesthesia or lumbar puncture has been performed, the following time interval between the last nadroparin injection and insertion or removal of the needle or catheter used for spinal or epidural anesthesia should be observed — at least 12 hours for therapeutic doses or 24 hours for prophylactic doses, considering drug characteristics and individual patient factors.

For patients with renal insufficiency, this interval may be extended.

In almost all cases, prophylactic LMWH treatment can be initiated 6–8 hours after anesthesia administration or catheter removal, provided adequate neurological monitoring is ensured.

Re-administration of nadroparin should be delayed until completion of the surgical procedure.

Patients should be regularly examined for early signs of neurological impairment, such as back pain, sensory or motor disturbances (numbness or weakness in legs), or bowel and/or bladder dysfunction. If signs of neurological impairment are detected, immediate treatment should be initiated.

The medical team should be trained to recognize these symptoms. Patients should be warned to immediately report any of these symptoms to their physician.

In case of suspected intraspinal hematoma, immediate diagnosis and initiation of treatment, including measures to reduce pressure on spinal cord tissue, are required.

In case of significant or obvious bleeding during catheter insertion, a careful benefit-risk assessment should be performed before starting or resuming heparin therapy.

Particular caution is required when other medicinal products affecting hemostasis (e.g., NSAIDs or aspirin) are used concomitantly.

Salicylates, nonsteroidal anti-inflammatory drugs, and platelet aggregation inhibitors

Concomitant use of nadroparin with acetylsalicylic acid, other salicylates, nonsteroidal anti-inflammatory drugs, and platelet aggregation inhibitors for prevention or treatment of venous thromboembolic complications or for prevention of blood clotting during hemodialysis is not recommended, as they may increase bleeding risk. If such combination cannot be avoided, careful clinical monitoring and laboratory tests should be performed.

In clinical trials of treatment for unstable angina and myocardial infarction without pathological Q wave on ECG, nadroparin was used in combination with acetylsalicylic acid at a dose not exceeding 325 mg/day (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").

Skin necrosis

Rare cases of skin necrosis have been reported. These were preceded by purpura or infiltrated painful erythematous lesions, with or without systemic symptoms. In such cases, treatment should be discontinued immediately.

Latex allergy

The protective cap on the needle of the pre-filled syringe contains latex, which may cause severe allergic reactions in individuals with latex allergy.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have not shown teratogenic or fetotoxic effects of Fraxiparine®.

Prophylactic use during the first trimester of pregnancy and treatment

Currently, there are insufficient clinical data to evaluate the potential teratogenic or fetotoxic effects of nadroparin in humans when used at prophylactic doses during the first trimester of pregnancy or at therapeutic doses throughout pregnancy.

Therefore, as a precautionary measure, it is advisable to avoid prescribing nadroparin at prophylactic doses during the first trimester of pregnancy and at therapeutic doses throughout pregnancy.

Prophylactic use during the second and third trimesters of pregnancy

In a limited number of patients, no teratogenic or fetotoxic effects were observed when nadroparin was used during the second and third trimesters of pregnancy. However, further clinical studies are needed to evaluate the effects of nadroparin in such cases.

Therefore, the use of nadroparin during the second and third trimesters of pregnancy is permitted only if necessary and only at prophylactic doses.

If epidural anesthesia is required, it is recommended, whenever possible, to discontinue prophylactic heparin therapy at least 12 hours before anesthesia.

Breastfeeding

Data on the excretion of nadroparin into breast milk are limited; therefore, the use of nadroparin during breastfeeding is not recommended.

Fertility

There are no clinical studies on the effect of Fraxiparine® on fertility.

Ability to affect reaction speed when driving or operating machinery

Currently, there are no data on the effect of nadroparin on the ability to drive or operate machinery.

Method of Administration and Dosage

SUBCUTANEOUSLY (except in cases of use during hemodialysis).

This medicinal formulation is intended for use in adult patients.

Fraxiparin® is not intended for intramuscular administration.

1 ml of Fraxiparin® corresponds to approximately 9500 IU anti-Xa of nadroparin calcium.

Due to the risk of heparin-induced thrombocytopenia, platelet counts must be monitored regularly throughout the entire treatment period (see section "Special Precautions").

Subcutaneous Injection Technique. The air bubble in the syringe should not be expelled prior to injection. Subcutaneous injection should preferably be administered while the patient is lying down. It is recommended to administer subcutaneous injections of Fraxiparin® alternately into the right and left anterolateral and posterolateral abdominal wall. The needle should be inserted perpendicularly, not at an angle, into a skin fold held between the thumb and index finger, and maintained throughout the injection.

Prevention of Venous Thromboembolic Complications in Surgery

These recommendations generally apply to surgical procedures performed under general anesthesia.

When spinal or epidural anesthesia is used, the benefit of administering the drug prior to surgery must be carefully weighed against the theoretical risk of spinal hematoma (see section "Special Precautions").

When nadroparin is used concomitantly with spinal or epidural anesthesia or lumbar puncture, established time intervals must be observed (see section "Special Precautions").

Frequency of Administration

1 injection per day.

Recommended Dose

The dose is determined based on the individual patient's risk level for thromboembolic complications and the type of surgical procedure.

Moderate Risk of Thromboembolic Complications

For surgical procedures associated with moderate thromboembolic risk and in the absence of high-risk factors in the patient, the effective prophylactic dose is 2850 IU anti-Xa (0.3 ml) once daily.

According to the standard regimen, the first dose should be administered 2 hours before surgery.

High Risk of Thromboembolic Complications

Hip or knee joint surgery – the dose is determined according to the patient's body weight. Administered once daily as follows:

• 38 IU anti-Xa/kg – preoperatively, 12 hours before surgery; postoperatively, 12 hours after surgery completion, and once daily during the first 3 postoperative days;
• 57 IU anti-Xa/kg, starting from the 4th postoperative day.

Table 1

Recommended dosing regimen according to patient body weight

Other cases

If there is an increased risk of thromboembolic complications related to the type of surgical procedure (especially in oncological surgery) and/or to the patient himself (especially in case of a history of thromboembolic disease), the adequate dose of nadroparin is 2850 IU (0.3 ml).

Duration of therapy

Treatment with LMWH, in combination with conventional methods of elastic compression of the lower limbs, should be continued until full recovery of the patient's activity and mobility.

For general surgical procedures, the duration of LMWH treatment should not exceed 10 days, except in cases of high risk of venous thromboembolic complications in individual patients (see section "Special precautions").

If the risk of venous thromboembolic complications persists after completion of the recommended treatment duration, further options for continuing prophylactic therapy should be considered, including the use of oral anticoagulants.

However, the clinical benefit of long-term treatment with LMWH or VKAs is currently not established.

Prevention of thromboembolism in patients with acute medical conditions

Nadroparin is administered subcutaneously once daily. Doses depend on the patient's body weight (see Table 2). Treatment should be continued throughout the period of thromboembolic risk.

Table 2

For elderly patients, it is advisable to reduce the dose to 0.3 ml (2850 IU anti-Xa).

Prevention of blood coagulation in the extracorporeal circulation circuit / during hemodialysis

INTRAVENOUSLY (into the arterial line of the dialysis circuit).

To prevent blood coagulation in the dialysis circuit, patients undergoing hemodialysis should receive an initial dose of the drug at 65 IU/kg administered into the arterial line of the dialysis circuit at the beginning of each session.

The drug dose is administered once intravenously as a bolus and is used for dialysis sessions lasting 4 hours or less. For subsequent dialysis sessions, the dose should be adjusted according to individual patient response and variability in effect both between patients and within the same patient.

Table 3

Recommended dosing regimen according to patient body weight

If necessary, the dose should be adjusted according to patient-specific characteristics or dialysis procedure conditions. In cases of high bleeding risk, half of the recommended drug dose may be administered.

Treatment of deep vein thrombosis (DVT)

If DVT is suspected, the diagnosis should be rapidly confirmed by appropriate diagnostic investigations.

Frequency of administration

2 injections per day (i.e., every 12 hours).

Recommended dose

The dose is 85 IU anti-Xa/kg.

Dosing of LMWH according to body weight has not been studied in patients with body weight greater than 100 kg or less than 40 kg. In patients with body weight exceeding 100 kg, the efficacy of LMWH treatment may be reduced; in patients with body weight less than 40 kg, the risk of bleeding may be increased. Close clinical monitoring is required.

Generally, the recommended dose according to patient body weight is 0.1 ml / 10 kg every 12 hours, as indicated in Table 4.

Table 4

The injected volume is adjusted by moving the plunger accordingly, while holding the syringe vertically.

Treatment duration for VTE

In the treatment with LMWH, transition to oral anticoagulants should be made as soon as possible, provided there are no contraindications. The duration of LMWH treatment should not exceed 10 days, including the stabilization period during transition to VKA, except in cases where stabilization difficulties occur (see section "Special precautions"). Thus, treatment with oral anticoagulants should be initiated as early as possible.

Treatment of unstable angina / non-Q-wave myocardial infarction

Nadroparin at a dose of 86 IU anti-Xa/kg body weight is administered subcutaneously twice daily at 12-hour intervals in combination with aspirin (recommended dose – 75−325 mg orally after a loading dose of at least 160 mg).

The initial dose is given as a single intravenous bolus injection followed by a subcutaneous injection of 86 IU anti-Xa/kg. Subsequent doses are administered subcutaneously.

The recommended treatment duration is approximately 6 days; therapy should continue until clinical stabilization is achieved. Dose calculation is based on the patient's body weight (see Table 5).

Table 5

Due to the lack of clinical data on the concomitant use of nadroparin with thrombolytics, in case thrombolytic therapy is required, it is recommended to discontinue nadroparin and initiate the necessary therapy according to standard practice.

Special patient groups

Renal impairment

Prophylaxis of thromboembolic complications

Dose adjustment is not required in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min).

Moderate or severe renal impairment is associated with increased effects of nadroparin. These patients have an increased risk of thromboembolism and bleeding.

If dose reduction is considered appropriate for patients with moderate renal impairment (creatinine clearance ≥ 30 mL/min and < 50 mL/min) based on individual risk factors for bleeding and thromboembolism, the dose should be reduced by 25–33% (see sections "Pharmacokinetics" and "Dosage and administration").

In patients with severe renal impairment (creatinine clearance < 30 mL/min), the dose should be reduced by 25–33% (see sections "Pharmacokin游戏副本

Adverse reactions.

The adverse reactions listed below are classified by organs and systems and by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), unknown (frequency cannot be estimated from available data).

Blood and lymphatic system

Very common: bleeding of various localizations, occurring more frequently in patients with risk factors such as organic organ lesions with tendency to bleeding, concomitant use of certain medicinal products (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"), advanced age, renal impairment, low body weight, non-compliance with the recommended treatment regimen, especially regarding duration of treatment and doses calculated based on patient's body weight (see section "Special precautions for use").

Rare: intraspinal hematoma — may occur with concomitant use of LMWH, spinal anesthesia, analgesia or epidural anesthesia; thrombocytopenia (see section "Special precautions for use"), thrombocytosis (asymptomatic and reversible increase in platelet count). There are two types of thrombocytopenia:

• Type I, which is more common — moderate decrease in platelet count > 100,000/mm³, developing early (within 5 days of therapy) and not requiring discontinuation of the drug;
• immune-mediated thrombocytopenia (HIT) type II, which is rare and sometimes complicated by arterial or venous thrombosis. Its frequency has not yet been established (see section "Special precautions for use").

Very rare: eosinophilia (isolated or associated with skin lesions), reversible upon discontinuation of treatment.

Immune system

Very rare: immediate-type hypersensitivity reactions (including angioedema, skin reactions, bronchospasm and anaphylactic shock), sometimes requiring discontinuation of the drug.

Nervous system

Unknown: headache, migraine.

Metabolism and digestive disorders

Very rare: reversible hyperkalemia associated with heparin-induced suppression of aldosterone secretion, mainly in patients with risk factors (see section "Special precautions for use").

Hepatobiliary system

Common: increased liver transaminase activity, usually reversible.

Reproductive system and breast

Very rare: priapism.

Skin and subcutaneous tissue

Rare: rash, urticaria, erythema, pruritus.

Very rare: skin necrosis, mainly at injection site (see section "Special precautions for use").

Musculoskeletal and connective tissue

With long-term use of LMWH, as with unfractionated heparin therapy, osteoporosis risk cannot be excluded.

General disorders and injection site conditions

Very common: hematomas at injection site. Such hematomas occur if injection technique is not followed or inappropriate materials are used for injection.

In some cases, hard nodules due to inflammation may appear; these do not indicate heparin encapsulation and disappear within several days. Their appearance does not require discontinuation of the drug.

Common: injection site reactions (including inflammation, pruritus and erythema). Rare cases of type IV hypersensitivity reactions and delayed-type hypersensitivity reactions in the form of contact eczema have been reported.

Rare: calcinosis at injection site.

Calcinosis occurs more frequently in patients with altered calcium-phosphate metabolism, e.g. in chronic renal failure.

Very rare: skin necrosis at injection site.

This reaction may be preceded by infiltrated or painful erythematous plaques or purpura. In case of skin necrosis, nadroparin should be discontinued immediately.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store below 30 °C. Keep out of reach of children.

Incompatibilities. Do not mix with other medicinal products.

Packaging. 2 pre-filled glass syringes with safety system in a blister; 5 blisters in a cardboard box.

Injectable solutions in pre-filled syringes contain:

Category of supply. By prescription only.

Manufacturer.

Aspen Notre Dame de Bondeville.

Aspen Notre Dame de Bondeville.

Manufacturer's address and address of its place of business.

1, rue de l'Abbaye, 76960 Notre Dame de Bondeville, France.