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 (0.3 ml) contains 2850 IU anti-Xa of nadroparin calcium;

1 pre-filled syringe (0.4 ml) contains 3800 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: transparent or slightly opalescent, colorless or light yellow solution practically free from visible particles – at the time of release;

from transparent to slightly opalescent, colorless or light yellow, or slightly brownish or slightly dark yellow solution practically free from visible particles – at the end of shelf life.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01A B06.

Pharmacological Properties

Pharmacodynamics

Nadroparin is a low-molecular-weight heparin (LMWH) in which antithrombotic activity and anticoagulant activity of standard heparins are not directly correlated. It has higher anti-Xa activity than anti-IIa or antithrombin activity. For nadroparin, the ratio of these two types of activity ranges from 2.5 to 4. At prophylactic doses, nadroparin does not significantly affect activated partial thromboplastin time (aPTT). At therapeutic doses, nadroparin may prolong aPTT by 1.4 times compared to the control value. This prolongation reflects the residual antithrombin activity of nadroparin.

Pharmacokinetics

Pharmacokinetic parameters are evaluated based on the plasma anti-Xa activity profile.

Availability

After subcutaneous administration, absorption is rapid and nearly complete (approximately 100%). Peak plasma activity levels are observed between 3 and 4 hours after administration when nadroparin is given twice daily. When nadroparin is administered once daily, the peak occurs between 4 and 6 hours after injection.

Metabolism

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

Distribution

After subcutaneous administration, the elimination half-life of anti-Xa activity of low-molecular-weight heparins is longer than that of unfractionated heparins, averaging approximately 3–4 hours. Anti-IIa activity declines more rapidly in plasma than anti-Xa activity of low-molecular-weight heparins.

Excretion

Excretion is primarily renal, with minimal metabolism.

Special Populations

Elderly Patients

In elderly individuals, renal function is physiologically reduced, leading to slower drug elimination. This does not affect dosing or administration regimen during prophylactic therapy if renal function remains within acceptable limits, i.e., when the reduction is mild. Renal function should be systematically assessed using the Cockcroft formula before initiating LMWH therapy in patients over 75 years of age (see section "Special Warnings and Precautions for Use").

Renal Impairment

In a pharmacokinetic study, 5 patients with moderate renal impairment, 7 patients with severe renal impairment, and 7 patients undergoing hemodialysis received a single intravenous dose of nadroparin. A correlation was observed 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. Mean plasma clearance of nadroparin in these patients was reduced by 63% compared to normal.

In patients with severe renal impairment (creatinine clearance 10–20 mL/min), mean AUC and elimination half-life increased by 95% and 112%, respectively, compared to healthy volunteers. Plasma clearance was reduced by 50% compared to patients with normal renal function. This study showed considerable inter-individual variability.

In patients undergoing hemodialysis, low-molecular-weight heparin was administered into the arterial line of the hemodialysis circuit at appropriate doses to prevent clotting in the circuit. Between two hemodialysis sessions, in patients with severe renal impairment on hemodialysis (creatinine clearance 3–6 mL/min), mean AUC and elimination half-life increased by 62% and 65%, respectively, compared to healthy volunteers. Plasma clearance in these patients was reduced by 67% compared to patients with normal renal function (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").

In cases of overdose, systemic absorption of nadroparin may lead to high anti-Xa activity, which is associated with terminal renal failure.

Clinical characteristics.

Indications.

Prevention of thromboembolic complications, namely:

• 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;
• venous thromboembolic disease in surgical procedures associated with moderate to high risk of 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 acute myocardial infarction (AMI) without pathological Q-wave on ECG, in combination with acetylsalicylic acid.

Contraindications.

Nadroparin is contraindicated in cases of:

• hypersensitivity to nadroparin, heparin or its derivatives, including low-molecular-weight heparins, or to any of the excipients;
• severe heparin-induced thrombocytopenia type II previously caused by unfractionated heparin or low-molecular-weight heparin, as well as history of nadroparin-induced thrombocytopenia (see section "Special precautions");
• episodes of bleeding or predisposition to bleeding associated with coagulation disorders (disseminated intravascular coagulation may be an exception to this rule if not related to heparin therapy) (see section "Special precautions");
• organic lesions with risk of bleeding (e.g. active peptic ulcer);
• acute hemorrhagic stroke;
• lack of data in patients with severe renal impairment (defined as creatinine clearance < 30 mL/min according to Cockcroft’s formula) when used at therapeutic doses for treatment of deep vein thrombosis, thromboembolic events, unstable angina, and myocardial infarction without pathological Q-wave, except during hemodialysis;
• epidural or spinal anesthesia is contraindicated if LMWH is used for treatment;
• acute infective endocarditis (except certain embolic cardiopathies);
• the drug is contraindicated in pediatric patients (under 18 years of age).

Therapeutic doses of this medicinal product are generally not recommended in the following cases:

• acute phases of extensive ischemic stroke, with or without impaired consciousness; if the stroke is embolic in origin, administration of the drug should be delayed for 72 hours; however, efficacy of LMWH at therapeutic doses has not been established to date, regardless of the cause, extent of lesion, or clinical severity of ischemic stroke;
• use of nadroparin is generally not recommended in patients with mild or moderate renal impairment; however, if its use is considered necessary in these cases, the following should be considered:
• if the physician considers dose reduction appropriate for patients with mild to moderate renal impairment, taking into account individual risk factors for bleeding and thromboembolic complications (creatinine clearance ≥ 30 mL/min and < 50 mL/min), the dose should be reduced by 25–33% (see sections "Pharmacokinetics", "Special precautions", and "Dosage and administration");
• dose reduction is not required for patients with mild renal impairment (creatinine clearance ≥ 50 mL/min) (see section "Dosage and administration").

Additionally, this medicinal product at therapeutic doses is generally not recommended for any patients, regardless 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;
• non-steroidal anti-inflammatory drugs (NSAIDs) (systemic administration);
• dextran 40 (parenteral administration).

Nadroparin at prophylactic doses is generally not recommended in the following cases:

• severe renal impairment (creatinine clearance approximately 30 mL/min according to Cockcroft’s formula); however, if use is considered necessary in this situation, and if, considering individual risk factors for bleeding or thromboembolic complications, dose reduction is deemed appropriate by the treating physician, the dose should be reduced by 25–33% (see sections "Pharmacokinetics", "Special precautions", and "Dosage and administration");
• intracranial hemorrhage – during the first 24 hours.

Additionally, this medicinal product at prophylactic doses is generally 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;
• NSAIDs (systemic administration);
• dextran 40 (parenteral administration).

Interaction with other medicinal products and other forms of interaction.

Some medicinal products and classes of drugs increase the risk of hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, NSAIDs, heparins (low-molecular-weight or unfractionated), cyclosporine, and tacrolimus, trimethoprim.

Development of hyperkalemia may depend on the presence of concomitant risk factors.

This risk increases when combined with the above-listed medicinal products.

Combinations not recommended

Use of LMWH at therapeutic doses in patients under 65 years of age and use of LMWH at any doses in elderly patients (> 65 years).

When combined with acetylsalicylic acid at analgesic doses, other salicylates, anti-inflammatory agents (NSAIDs and systemic glucocorticoids), and antiplatelet agents (abciximab, acetylsalicylic acid at antiplatelet doses for cardiovascular and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban), there is an increased risk of bleeding (due to platelet function inhibition and gastrointestinal mucosal damage by salicylates and NSAIDs).

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

In clinical studies treating unstable angina or myocardial infarction without pathological Q-wave, nadroparin was administered in combination with aspirin at doses up to 325 mg per day (see sections "Special precautions" and "Dosage and administration"). If combination with NSAIDs cannot be avoided, careful clinical monitoring is recommended.

When combined with dextran 40 (parenterally), there is an increased risk of bleeding (due to platelet function inhibition by dextran 40).

Combinations requiring precautions during use

Nadroparin should be used with caution in patients receiving oral anticoagulants, as this combination leads to potentiation of anticoagulant effect.

When replacing heparin with an oral anticoagulant, intensified clinical monitoring is required, and nadroparin therapy should be continued until the INR (International Normalized Ratio) is stabilized at the target value.

Combinations to be used with caution

Concomitant use of agents affecting hemostasis at different levels increases the risk of bleeding. Therefore, regardless of patient age, the risk of combining prophylactic-dose LMWH with oral anticoagulants, antiplatelet agents (abciximab, NSAIDs, acetylsalicylic acid at any dose, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban), and thrombolytic agents should be carefully evaluated through clinical and, if possible, biological monitoring.

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 the patient’s history of hypersensitivity reactions to unfractionated heparin should be performed.

Although the concentration of various LMWH-containing products is expressed in anti-Xa international units, their efficacy is not limited solely to anti-Xa activity. Therefore, it is dangerous to substitute one LMWH for another LMWH or for another type of synthetic polysaccharide using the same dosing regimen, since each of these medicinal products has a specific dosing schedule validated in dedicated clinical trials. Thus, additional safety measures and specific instructions for use of each medicinal product must be strictly followed.

Bleeding risk

It is extremely important to adhere strictly to the recommended treatment regimen (dosing schedule and duration of treatment). Otherwise, bleeding may occur, particularly in patients with risk factors (advanced age, renal impairment, etc.).

Specifically, severe bleeding has been observed:

• in elderly patients, particularly due to age-related decline in renal function;
• in patients with renal impairment;
• in patients with body weight less than 40 kg;
• when treatment duration exceeds the recommended average duration (10 days);
• when recommended therapeutic parameters have not been followed (including treatment duration and dose adjustment according to body weight);
• when used concomitantly with medicinal products that increase bleeding risk (see section "Interaction with other medicinal products and other forms of interaction").

Special monitoring is mandatory for all elderly patients and/or those with renal impairment, as well as for treatment durations exceeding 10 days.

Measurement of anti-Xa activity may be used in certain cases to detect accumulation (see "Biological monitoring").

Risk of heparin-induced thrombocytopenia

Due to the risk of heparin-induced thrombocytopenia (HIT), platelet counts should be monitored regularly throughout the entire treatment course.

Isolated cases of thrombocytopenia, sometimes severe, have been reported, which may be associated with arterial or venous thrombosis.

This diagnosis should be considered in the following situations:

• thrombocytopenia;
• any significant decrease in platelet count (from 30% to 50% compared to baseline) and/or platelet count < 150,000/mm³ (or 150 × 10⁹/L);
• occurrence of thrombosis during treatment (phlebitis, pulmonary embolism, acute limb ischemia, or even myocardial infarction or ischemic stroke);
• worsening of pre-existing thrombosis during treatment;
• disseminated intravascular coagulation.

In such cases, the likelihood of HIT is high, and platelet count should be checked immediately. Treatment with nadroparin should be discontinued.

Use in children

Due to insufficient data on the use of LMWHs in children, their use is not recommended.

Renal function

Nadroparin is primarily eliminated via the kidneys, resulting in increased nadroparin exposure in patients with renal impairment (see section "Pharmacokinetics"). The risk of bleeding is increased in patients with impaired renal function; therefore, treatment should be administered with caution.

The decision on whether dose reduction is necessary in patients with creatinine clearance between 30 and 50 mL/min should be based on the physician’s clinical assessment of individual bleeding risk versus thromboembolic risk (see section "Dosage and administration").

Renal function should be assessed prior to initiating LMWH treatment, especially in patients aged over 75 years, by calculating creatinine clearance (CrCl) using the Cockcroft formula with current body weight values.

For men: CrCl = (140 – age) × body weight / (0.814 × serum creatinine), where age is in years, body weight in kg, and serum creatinine in µmol/L.

For women, the result is multiplied by 0.85. If serum creatinine is expressed in mg/dL, the result should be multiplied by 8.8.

LMWH use is contraindicated as treatment in cases of severe renal impairment (CrCl approximately 30 mL/min) (see section "Contraindications").

Biological monitoring

Monitoring platelet levels in patients receiving LMWH and risk of developing HIT (or HIT type II)

To optimally detect HIT, patient monitoring should be performed as follows:

• In surgical procedures or recent trauma (within the last 3 months): due to HIT frequency > 0.1% or even > 1%, systematic biological monitoring of all patients is required, regardless of whether the medicinal product is used for prophylaxis or treatment. This includes monitoring of platelet levels:
• before initiation of LMWH treatment or no later than within the first 24 hours after treatment initiation;
• then twice weekly for one month (the period of highest risk);
• then once weekly until the end of treatment in cases of prolonged therapy.
• In the absence of recent surgery or trauma (within the last 3 months): systematic biological monitoring is required both for prophylaxis and treatment, following the same instructions as for surgical procedures and trauma (see above), in patients:
• with a history of unfractionated heparin or LMWH use within the last 6 months, considering HIT frequency > 0.1% or even > 1%;
• with significant comorbidities, considering the potential severity of HIT in these patients.

In other cases, considering the lower frequency of HIT (< 0.1%), the frequency of platelet monitoring may be reduced to:

• one platelet count at the beginning of treatment or no later than within the first 24 hours after treatment initiation;
• platelet count if any clinical signs suggestive of HIT occur (any new arterial and/or venous thromboembolic events, any painful skin lesions at the injection site, any allergic or anaphylactoid reactions during treatment); patients should be informed about the possibility of such events and advised to contact their physician if necessary;
• HIT should be suspected if platelet count is < 150,000/mm³ (or 150 × 10⁹/L), and/or if relative platelet count reduction is approximately 50% or even 30% from the pre-treatment level;
• dose reduction is not required in patients with mild renal impairment (CrCl ≥ 50 mL/min) (see section "Dosage and administration").

The effects of HIT are likely of immune-allergic nature and typically occur between the 5th and 21st day of heparin therapy (with peak incidence around day 10). However, it may occur earlier if there is a history of heparin-associated thrombocytopenia, and isolated cases have been reported after day 21.

If necessary, nadroparin treatment may be considered in patients with a history of thrombocytopenia (except for HIT type II, see section "Contraindications") related to heparin (unfractionated or low molecular weight). In such cases, careful clinical observation and platelet count assessment at least once daily are required. If thrombocytopenia occurs, treatment should be discontinued immediately.

In case of thrombocytopenia during heparin use (both standard and low molecular weight), replacement of heparin with antithrombotic agents of another class should be considered. If such an antithrombotic agent is unavailable, substitution with another LMWH product 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, since cases of continuation of initial thrombocytopenia after product substitution have been described (see section "Contraindications").

Therefore, a careful patient history regarding any previous episodes should be obtained before initiating treatment.

Manifestation of HIT is always an emergency and requires specialized care.

Any significant decrease in platelet count (from 30% to 50% from baseline) should be considered a warning sign that this parameter may reach a critical level. If decreased platelet count is detected, the following measures must be taken:

1. Platelet count should be determined immediately.
2. Heparin treatment should be discontinued, if decreased platelet count is confirmed and progressing, according to test results, and no other obvious causes are present.

A blood sample should be placed in a citrate tube for in vitro platelet aggregation and immunological testing. However, emergency measures required in such situations should not await results of in vitro platelet aggregation or immunological tests, as such tests are only routinely performed in specialized laboratories and results may take several hours at best. Nevertheless, such tests should be performed to assist in diagnosing this complication, as continued heparin therapy is associated with increased thrombosis risk.

1. Prevention or treatment of thrombotic complications of HIT should be initiated.

If continuation of anticoagulant therapy is considered necessary, heparin should be replaced with an antithrombotic agent of another class – danaparoid sodium or lepirudin – administered at prophylactic or therapeutic doses as appropriate.

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 exacerbating thrombotic effects.

Replacing heparin with VKA

• Clinical and biological monitoring (prothrombin time expressed as INR) should be intensified to control the effect of VKA.
• Due to the latent period before full VKA effect develops, heparin should be continued at equivalent doses for as long as necessary to maintain INR, determined by two consecutive tests, within the target range.

Anti-Xa activity assay

Most clinical trials confirming LMWH efficacy were conducted using weight-adjusted dosing without specific laboratory monitoring; therefore, the utility of biological monitoring as a control method for assessing LMWH efficacy has not been established. However, laboratory monitoring based on anti-Xa activity measurement may be useful for assessing bleeding risk in certain clinical situations, often associated with increased overdose risk.

These situations typically occur when therapeutic-dose LMWH is indicated due to appropriate dosing, as well as in cases of:

• mild to moderate renal impairment (creatinine clearance calculated using the Cockcroft formula approximately 30–60 mL/min): unlike unfractionated heparin, LMWHs are primarily eliminated by the kidneys, so any renal impairment may lead to relative overdose; however, therapeutic-dose LMWH is contraindicated in severe renal impairment (see section "Contraindications");
• body weight differing from normal (low weight or even cachexia, obesity);
• unexplained bleeding.

Conversely, laboratory monitoring is not recommended when prophylactic doses are used, provided LMWH treatment complies with recommended therapeutic parameters (especially treatment duration), and during hemodialysis.

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

• approximately 4 hours after the 3rd dose if the drug is administered subcutaneously twice daily;
• approximately 4 hours after the 2nd dose if the drug is administered subcutaneously once daily.

Repeat anti-Xa activity testing to measure heparin blood levels (e.g., every 2–3 days) should be considered on a case-by-case basis depending on prior test results, and potential dose adjustments of LMWH should be evaluated.

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

For example, for nadroparin, according to available data, mean values (± standard deviation) of activity observed 4 hours after administration are:

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

These mean values were obtained in clinical trials measuring anti-Xa activity using a chromogenic (amidolytic) method.

Activated partial thromboplastin time (aPTT)

Some LMWHs may cause a moderate prolongation of aPTT. Since this effect has no proven clinical significance, any monitoring based on this test is ineffective.

Spinal/epidural anesthesia during prophylactic use of LMWH

As with other anticoagulants, rare cases of spinal hematomas leading to permanent or irreversible paralysis have been reported with LMWH use during spinal or epidural anesthesia.

The risk of spinal or epidural hematomas appears higher when epidural catheters are inserted or when other medicinal products affecting hemostasis (e.g., NSAIDs, antiplatelet agents, or other anticoagulants) are used concomitantly. Risk is also increased with repeated lumbar punctures and traumatic lumbar puncture.

Therefore, the decision on concomitant use of neuraxial blockade and anticoagulant therapy should be made after careful evaluation of individual benefit-risk balance in such cases:

• in patients already receiving anticoagulants, the benefit of neuraxial blockade should be carefully weighed against the risk;
• in patients scheduled for non-emergency surgical procedures with planned neuraxial blockade, the benefit of anticoagulant therapy should be carefully weighed against the risk.

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

Longer intervals may be considered for patients with renal impairment.

In almost all cases, prophylactic LMWH treatment may be initiated 6–8 hours after the procedure or catheter removal, under close neurological monitoring.

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

Patients should be monitored frequently for symptoms of neurological deficit such as back pain, sensory or motor disturbances (numbness or weakness in legs), or bowel and/or bladder dysfunction. In case of neurological impairment, emergency treatment is required.

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 spinal hematoma, emergency diagnosis and treatment, including spinal cord decompression, should be initiated.

If significant or obvious bleeding occurs during catheter insertion prior to starting or resuming heparin therapy, a careful benefit-risk assessment should be performed.

Particular attention should be paid when other medicinal products affecting hemostasis (i.e., NSAIDs, aspirin) are used concomitantly.

Situations associated with certain risks

Monitoring should be intensified during treatment in the following cases due to increased bleeding risk:

• hepatic impairment;
• severe arterial hypertension;
• gastrointestinal ulcers or any other organic lesions with bleeding tendency in history;
• choroidal or retinal vascular diseases;
• postoperative period after brain, spinal cord, or eye surgery;
• hyperkalemia;
• all pros and cons should be carefully considered before performing lumbar puncture, considering the risk of intraspinal bleeding. If possible, lumbar puncture should be postponed.

Heparin may suppress aldosterone secretion and lead to hyperkalemia.

This has been observed primarily in patients with elevated serum potassium levels and in patients with risk factors (diabetes mellitus, chronic renal failure, previously diagnosed metabolic acidosis, or treatment with agents that may increase potassium levels, e.g., ACE inhibitors and NSAIDs).

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

Salicylates, NSAIDs, and platelet aggregation inhibitors

Concomitant use of acetylsalicylic acid, other salicylates, nonsteroidal anti-inflammatory drugs, and platelet aggregation inhibitors is not recommended for prevention or treatment of venous thromboembolic complications or for prevention of blood clotting during hemodialysis, as they may increase bleeding risk. If such combination use cannot be avoided, careful clinical monitoring and laboratory parameter control should be performed. In clinical trials of treatment for unstable angina and non-Q-wave myocardial infarction, nadroparin was used in combination with acetylsalicylic acid at a dose of 325 mg/day (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Skin necrosis

Very 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 nadroparin.

Prophylactic use in the first trimester of pregnancy and treatment

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

Therefore, as a precautionary measure, prophylactic doses of nadroparin should not be used during the first trimester of pregnancy, and therapeutic doses should not be used throughout pregnancy.

Prophylactic use in the second and third trimesters of pregnancy

Currently, in limited clinical experience with nadroparin use in a limited number of pregnant patients (second and third trimesters), no evidence of specific developmental abnormalities or fetotoxic effects has been observed. However, further studies are needed to evaluate the effects under the conditions mentioned above.

Therefore, the use of nadroparin at prophylactic doses in the second and third trimesters of pregnancy should not be considered except when therapeutic benefit outweighs potential risk.

If epidural anesthesia is planned, prophylactic heparin use should be temporarily discontinued, if possible, at least 12 hours before anesthesia.

Breastfeeding

Data on excretion of nadroparin into breast milk are limited. However, gastrointestinal absorption of nadroparin in the newborn is theoretically unlikely; therefore, nadroparin treatment is not contraindicated during breastfeeding.

Fertility

There are no clinical studies on the effect of nadroparin on fertility.

Ability to affect reaction speed when driving or operating machinery

There are no data on the effect of nadroparin on the ability to drive or operate machinery.

Method of Administration and Dosage

FOR SUBCUTANEOUS ADMINISTRATION (except for hemodialysis).

This medicinal product is intended for adults.

Do not use for intramuscular injections.

1 ml of Fraxiparine® corresponds to 9500 IU anti-Xa of nadroparin.

Subcutaneous Injection Technique

Do not remove the air bubble from the syringe before injection.

Nadroparin is administered by subcutaneous injection, preferably with the patient lying down. The injection should be given into the subcutaneous tissue of the anterior-lateral and posterior-lateral abdominal wall, alternating right and left sides.

The needle should be fully inserted perpendicularly—not at an angle—into a skin fold pinched between the thumb and index finger of the administrator. The skin fold must be held throughout the injection.

Since there is a risk of developing HIT (heparin-induced thrombocytopenia), platelet count should be monitored throughout the entire course of treatment (see section "Special Warnings and Precautions for Use").

Prophylaxis of Venous Thromboembolic Disease in Surgical Procedures

In general, these recommendations apply to surgical procedures performed under general anesthesia.

In the case of spinal or epidural anesthesia, the appropriateness of preoperative administration should be evaluated, considering the theoretical increased risk of spinal hematoma (see section "Special Warnings and Precautions for Use").

Special recommendations regarding time intervals between nadroparin administration and performance of spinal/epidural anesthesia or lumbar puncture must be followed (see section "Special Warnings and Precautions for Use").

Frequency of Administration

1 injection per day.

Dose Administered

Depends on the individual risk associated with each patient and type of surgical procedure.

Surgical Procedures Associated with Moderate Thromboembolic Risk

For surgical procedures associated with moderate risk of thrombosis and in patients without high risk of thromboembolism, effective prophylaxis of thromboembolic disease is achieved by daily administration of 2850 IU anti-Xa (0.3 ml).

The studied treatment regimen included administration of the first injection 2 hours before surgery.

Surgical Procedures Associated with High Thromboembolic Risk

Hip or knee surgery: the dose of nadroparin is adjusted according to the patient's body weight. The dose is administered once daily as follows:

• 38 IU anti-Xa/kg:
  • preoperatively, i.e., 12 hours before surgery;
  • postoperatively, 12 hours after completion of surgery, then once daily during the first 3 postoperative days;
• 57 IU anti-Xa/kg starting on the 4th postoperative day.

Table 1

General Dosage Recommendations According to Patient Body Weight

Other situations

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 themselves (especially in case of history of thromboembolic disease), the adequate dose of nadroparin is 2850 IU (0.3 ml).

Duration of treatment

Treatment with LMWH, in combination with standard methods of elastic compression of the lower limbs, should be continued until the patient is able to move actively and fully:

• in general surgical procedures, the duration of LMWH treatment should not exceed 10 days, except for individual cases of high risk of venous thromboembolic complications related to the patient (see section "Special precautions");
• if the risk of venous thromboembolic complications persists after completion of the recommended treatment duration, continuation of prophylactic therapy should be considered, in particular using oral anticoagulants.

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

Prophylaxis of venous thromboembolic disease in patients with acute medical conditions

Nadroparin is administered subcutaneously once daily. The dose should be selected according to the patient's body weight as shown in Table 2 below. Treatment should be continued throughout the entire period of thromboembolic risk.

Table 2

The dose may be reduced to 0.3 ml (2850 IU anti-Xa) for elderly patients.

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

INTRAVASCULAR ADMINISTRATION (into the arterial line of the dialysis circuit).

For patients undergoing regular hemodialysis, to prevent clot formation in the extracorporeal blood purification circuit, the drug should be administered at a dose of 65 IU/kg into the arterial line of the dialysis circuit at the beginning of the session.

This single intravascular bolus dose is intended only for dialysis sessions lasting 4 hours or less and should be subsequently adjusted according to the significant variability between patients and individual patient response.

Table 3

General dosing recommendations based on patient body weight

The dose should subsequently be adjusted according to the individual needs of each patient and the technical conditions of dialysis. In patients at risk of bleeding, dialysis sessions may be accompanied by administration of only half the dose.

Treatment of deep vein thrombosis (DVT)

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

Frequency of administration

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

Dose administered

The single 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 is increased. Special clinical monitoring is required.

General dosing recommendations according to patient body weight are 0.1 ml/10 kg every 12 hours, as indicated in Table 4.

Table 4

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

Treatment duration for VTE

When treating VTE, transition to oral anticoagulants should be initiated as early as possible, unless contraindicated. The duration of treatment with LMWH should not exceed 10 days, including the stabilization period during transition to VKAs, except in cases where stabilization is difficult (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 is administered subcutaneously twice daily (every 12 hours) at a dose of 86 IU anti-Xa/kg in combination with aspirin (recommended dosage: 75–325 mg orally after a minimum loading dose of 160 mg).

The initial dose should be given as an intravenous bolus injection followed by subcutaneous administration of 86 IU anti-Xa/kg. Subsequent doses are administered subcutaneously.

The recommended duration of treatment is approximately 6 days until clinical stabilization of the patient. Dose calculation is based on the patient's body weight as indicated in Table 5.

Table 5

If thrombolytic therapy is required and there are no clinical data on the concomitant use of nadroparin and thrombolytics, it is recommended to interrupt nadroparin treatment and manage the patient according to the standard regimen.

Special patient populations

Renal impairment

Prophylaxis of thromboembolic disease

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

Moderate and severe renal impairment are associated with increased nadroparin exposure. These patients have an increased risk of thromboembolic events and bleeding.

If the physician considers dose reduction appropriate for patients with moderate renal impairment (CrCl ≥ 30 mL/min and < 50 mL/min), taking into account individual risk factors for bleeding and thromboembolic complications, the dose should be reduced by 25–33% (see sections “Pharmacokinetics” and “Special warnings and precautions for use”).

For patients with severe renal impairment (CrCl < 30 mL/min), the dose should be reduced by 25–33% (see sections “Pharmacokinetics” and “Special warnings and precautions for use”).

Treatment of thromboembolic disease, unstable angina, and non-Q-wave myocardial infarction

Dose reduction is not required in patients with mild renal impairment (CrCl ≥ 50 mL/min).

Moderate and severe renal impairment are associated with increased nadroparin exposure. These patients have an increased risk of thromboembolic events and bleeding.

If the physician considers dose reduction appropriate for patients with moderate renal impairment (CrCl ≥ 30 mL/min and < 50 mL/min), taking into account individual risk factors for bleeding and thromboembolic complications, the dose should be reduced by 25–33% (see sections “Pharmacokinetics” and “Special warnings and precautions for use”).

Nadroparin is contraindicated in patients with severe renal impairment (see sections “Pharmacokinetics” and “Special warnings and precautions for use”).

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted.

Children

Fraxiparin® is not recommended for use in children, as there is insufficient data on safety and efficacy to determine dosing in this patient population.

Overdose

Accidental overdose following subcutaneous administration of high doses of LMWH may lead to hemorrhagic complications. Platelet count and other coagulation parameters should be monitored. Minor bleeding episodes rarely require specific treatment; usually, reducing or delaying the next dose of nadroparin is sufficient.

In cases of severe bleeding, protamine sulfate may sometimes be indicated, with the following considerations:

• protamine largely neutralizes the anticoagulant effect of nadroparin, but some anti-Xa activity remains;
• the efficacy of protamine is significantly lower compared to its effect in unfractionated heparin overdose;
• the benefit/risk ratio should be carefully evaluated before administering protamine sulfate, considering its potential adverse effects (including anaphylactic shock).

In such cases, neutralization should be performed by slow intravenous injection of protamine (sulfate or hydrochloride).

The required protamine dose depends on:

• the amount of heparin administered (100 antiheparin units of protamine neutralize the activity of 100 IU anti-Xa of LMWH);
• the time elapsed since heparin injection, based on which the antidote dose may be reduced.

Complete neutralization of anti-Xa activity, however, is not possible.

Furthermore, due to the absorption kinetics of LMWH, such neutralization may be transient; therefore, the total calculated dose of protamine should be divided into several injections (2 to 4) administered over 24 hours.

Oral ingestion of LMWH, even in large quantities (such cases have not been reported), is theoretically not expected to cause severe consequences due to very low gastrointestinal absorption.

Side effects

The adverse reactions listed below are classified by system organ class and 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), and not known (cannot be estimated from the available data).

Blood and lymphatic system

Very common: bleeding at various sites, occurring primarily in the presence of:

• concomitant risk factors: organic lesions with a tendency to bleed, certain drug combinations (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"), age, renal impairment, low body weight;
• failure to comply with therapeutic parameters, including duration of treatment and dose adjustment according to body weight (see section "Special warnings and precautions for use").

Rare:

• intraspinal haematomas may occur when LMWHs are used during spinal anaesthesia, analgesia, or epidural anaesthesia;
• thrombocytopenia (see section "Special warnings and precautions for use"). There are two types of thrombocytopenia:
• the most common Type I is usually mild (> 100,000/mm³), occurs early (within the first 5 days), and does not require discontinuation of treatment;
• rare cases of severe immune-mediated thrombocytopenia (HIT) Type II may sometimes be complicated by venous or arterial thrombosis; the frequency has not yet been adequately established (see section "Special warnings and precautions for use");
• thrombocytosis (asymptomatic and reversible increase in platelet count).

Very rare: hyper-eosinophilia, either isolated or associated with skin reactions, reversible upon discontinuation of treatment.

Immune system

Very rare: immediate-type allergic reactions (including skin reactions, angioneurotic oedema, bronchospasm, and even anaphylactic shock), which in some cases may require discontinuation of treatment.

Nervous system

Not known: headache, migraine.

Metabolism and digestive disorders

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

Hepatobiliary system

Common: increased levels of liver transaminases, usually reversible.

Reproductive system and breast

Very rare: priapism.

Skin and subcutaneous tissue

Rare: rash, urticaria, erythema, pruritus.

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

Musculoskeletal and connective tissue

Osteoporosis cannot be ruled out, as it may occur with prolonged treatment with unfractionated heparins.

General disorders and administration site conditions

Very common: haematoma at the injection site.

These reactions may be intensified if proper injection technique is not followed or if injection materials not meeting requirements are used.

In some cases, firm nodules may appear, reflecting an inflammatory process and not indicating heparin accumulation. These nodules usually disappear within a few days and do not require discontinuation of treatment.

Common: reactions at the injection site (including inflammation, pruritus, erythema).

Hypersensitivity reactions of Type IV and delayed-type hypersensitivity reactions, manifesting as contact eczema, have also been reported less frequently.

Rare: calcinosis at the injection site.

Calcinosis occurs more frequently in patients with altered calcium-phosphate levels, such as in chronic renal failure.

Very rare: skin necrosis at the injection site.

Such reactions may be preceded by purpura or painful infiltrated erythematous plaques. Treatment should be discontinued immediately.

Reporting of suspected adverse reactions

It is very important to report suspected adverse reactions after a medicinal product has been authorized, as this allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children. Do not store in the refrigerator. Do not freeze.

Incompatibilities. Do not mix with other medicinal products.

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

Solutions for injection in pre-filled syringes contain:

Prescription category. By prescription.

Manufacturer.

Aspen Notre Dame de Bondéville, France.

Manufacturer's location and address of its business operations.

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