Nadroparin (Fraxiparine) is a low molecular weight heparin that inhibits the activation of thrombin by factor Xa.

Nadroparin Uses:

Note: Not approved in the US

Fraxiparine:

• Acute coronary syndromes:

  • Used for treatment of unstable angina and non-ST-elevation myocardial infarction (NSTEMI) myocardial infarction (ie, non-Q wave MI)

• Anticoagulation during hemodialysis:

  • Prevention of clotting during hemodialysis

• Deep vein thrombosis:

  • Treatment of deep vein thrombosis (DVT).
  • Note: In patients with venous thromboembolism (VTE) (ie, DVT or PE) and without cancer, oral anticoagulants are preferred over LMWH (unless LMWH is used as initial parenteral anticoagulation prior to dabigatran, edoxaban, or while initiating warfarin).
  • In patients with venous thromboembolism (VTE) (ie, DVT or PE) and cancer, ACCP recommends LMWH over oral anticoagulants for initial and long-term treatment.

• Thromboprophylaxis:

  • Prophylaxis of thromboembolic disorders (particularly DVT and pulmonary embolism [PE]) in general and orthopedic surgery, high-risk medical patients (respiratory failure and/or respiratory infection and/or cardiac failure) immobilized due to acute illness or hospitalized in Intensive care unit (ICU).

• Fraxiparine Forte:

  • Treatment of deep vein thrombosis (DVT)

Nadroparin (Fraxiparine) Dose in Adults

Note: Dose expressed as anti-Xa international units

Nadroparin (Fraxiparine) Dose in the treatment of Acute coronary syndromes (unstable angina and NSTEMI [non-Q-wave myocardial infarction] in conjunction with aspirin):

Initial: Intravenous:

• Weight-based dosing:

  • 86 units/kg one time bolus (maximum dose: 9,500 units).

• Fixed dosing:

  • <50 kg:
    • 3,800 units one-time bolus
  • 50 to 59 kg:
    • 4,750 units one-time bolus
  • 60 to 69 kg:
    • 5,700 units one-time bolus
  • 70 to 79 kg:
    • 6,650 units one-time bolus
  • 80 to 89 kg:
    • 7,600 units one-time bolus
  • 90 to 99 kg:
    • 8,550 units one-time bolus
  • ≥100 kg:
    • 9,500 units one-time bolus

• Maintenance: SubQ:

Note: Begin 12 hours after the initial bolus.

• Usual treatment duration:
  • Six days; plasma anti-Xa levels should be less than 1.2 anti-Xa units/mL three to four hours postinjection.

    • Weight-based dosing:

      • 86 units/kg every twelve hours (maximum dose: 19,000 units/day)

    • Fixed dosing:

      • <50 kg:
        • 3,800 units every twelve hours
      • 50 to 59 kg:
        • 4,750 units every twelve hours
      • 60 to 69 kg:
        • 5,700 units every twelve hours
      • 70 to 79 kg:
        • 6,650 units every twelve hours
      • 80 to 89 kg:
        • 7,600 units every twelve hours
      • 90 to 99 kg:
        • 8,550 units every twelve hours
      • ≥100 kg:
        • 9,500 units every twelve hours

Nadroparin (Fraxiparine) Dose in the treatment of Anticoagulation during hemodialysis:

Note:

• Administer into the arterial line at the start of each dialysis session
• May give additional dose if the session lasts longer than 4 hours
• Adjust dose during subsequent dialysis sessions to plasma anti-Xa levels of 0.5 to 1 anti-Xa units/mL

• Weight-based dosing:

  • Initial: ~65 units/kg single dose (initial maximum dose: 5,700 units)

• Fixed dosing:

  • <50 kg:

    • 2,850 units 1 dose

  • 50 to 69 kg:

    • 3,800 units 1 dose

  • ≥70 kg:

    • 5,700 units 1 dose

Patients at risk of hemorrhage:

Note:

• Doses may be halved.
• Administer into the arterial line at the start of each dialysis session
• May give an additional smaller dose if the session lasts longer than 4 hours
• Adjust dose during subsequent dialysis sessions to plasma anti-Xa levels of 0.2 to 0.4 anti-Xa units/mL.

• Weight-based dosing:

  • Initial: ~32.5 units/kg 1 dose (initial maximum dose: 2,850 units)

• Fixed dosing:

  • <50 kg:

    • 1,425 units 1 dose

  • 50 to 69 kg:

    • 1,900 units 1 dose

  • ≥70 kg:

    • 2,850 units 1 dose

Nadroparin (Fraxiparine) Dose in the treatment of DVT: 

Note:

• In patients with VTE and without cancer, oral anticoagulants are preferred over LMWH (unless LMWH is used as initial parenteral anticoagulation prior to dabigatran, edoxaban, or while initiating warfarin).
• In patients transitioning to warfarin, start warfarin on the first or second treatment day and continue nadroparin until INR is ≥2 for at least 24 hours (usually 5 to 7 days).

• Weight-based dosing:

  • Bleeding risk is not increased:

    • 171 units/kg SubQ once a day (maximum dose: 17,100 units/day);
    • expected plasma anti-Xa levels are 1.2 to 1.8 anti-Xa units/mL three to four hours postinjection.

  • Bleeding risk is increased:

    • 86 units/kg every twelve hours (maximum dose: 17,100 units/day);
    • expected plasma anti-Xa levels are 0.5 to 1.1 anti-Xa units/mL three to four hours postinjection.

• Fixed dosing:

  • No increased risk for bleeding:

    • 40 to 49 kg:

      • 7,600 units once a day

    • 50 to 59 kg:

      • 9,500 units once a day

    • 60 to 69 kg:

      • 11,400 units once a day

    • 70 to 79 kg:

      • 13,300 units once a day

    • 80 to 89 kg:

      • 15,200 units once a day

    • ≥90 kg:

      • 17,100 units once a day

  • Increased risk for bleeding:

    • 40 to 49 kg:

      • 3,800 units every twelve hours

    • 50 to 59 kg:

      • 4,750 units every twelve hours

    • 60 to 69 kg:

      • 5,700 units every twelve hours

    • 70 to 79 kg:

      • 6,650 units every twelve hours

    • 80 to 89 kg:

      • 7,600 units every twelve hours

    • ≥90 kg:

      • 8,550 units every twelve hours

    • Obesity:

      • To calculate dose actual body weight should be used; a fixed upper dose limit is not recommended; however, increased monitoring may be warranted (see monitoring parameters) (Nutescu 2009).

  • Duration of therapy:

    • Based on the cause of VTE, the risk of recurrence, and risk of bleeding.
    • For specific recommendations refer to guidelines.

Nadroparin (Fraxiparine) Dose in the Thromboprophylaxis:

• General surgery:

  • Initial: 2,850 units subQ administered two to four hours preoperative
  • Maintenance: SubQ: 2,850 units once a day.
  • Continue therapy for at least seven days and until ambulant or no longer at DVT risk.

• High-risk medical patients (respiratory failure and/or respiratory infection and/or cardiac failure):

  • ≤70 kg:

    • 3,800 units once a day during the risk period of thromboembolism

  • >70 kg:

    • 5,700 units once a day during the risk period of thromboembolism

• Dose in Hip replacement surgery:

Note:

• For at least ten days continue therapy and until ambulant or no longer at DVT risk.

  • Weight-based dosing:

    • Initial: 38 units/kg (maximum dose: 3,800 units) twelve hours before and after surgery, followed by 38 units/kg once a day (maximum: 3,800 units/day) up to and including postoperative day three
    • On a postoperative day four, begin 57 units/kg once a day.
    • The maximum dose: 5,700 units/day.

  • Fixed dosing:

    • <50 kg:

      • 1,900 units twelve hours before and after surgery, followed by 1,900 units once a day up to and including postoperative day three; on a postoperative day 4, begin 2,850 units once a day

    • 50 to 69 kg:

      • 2,850 units twelve hours before and after surgery, followed by 2,850 units once a day up to and including postoperative day three; on a postoperative day 4, begin 3,800 units once a day

    • ≥70 kg:

      • 3,800 units twelve hours before and after surgery, followed by 3,800 units once a day up to and including postoperative day three; on a postoperative day four, begin 5,700 units once a day
    • Obesity:
      • In morbidly obese patients (BMI ≥40 kg/m²), increasing the prophylactic dose by 30 percent may be appropriate for some indications.

Nadroparin (Fraxiparine) Dose in Childrens

The safety and efficacy of the drug in children have not been established.

Pregnancy Risk Category: B

• Limited information is there related to the placental transfer.
• In pregnant women, LMWH is recommended over unfractionated heparin for the treatment of acute venous thromboembolism (VTE).
• LMWH is also recommended over unfractionated heparin for VTE prophylaxis in pregnant women with certain risk factors (eg, homozygous factor V Leiden, antiphospholipid antibody syndrome with ≥3 previous pregnancy losses).
• For women undergoing assisted reproduction therapy prophylaxis is not routinely recommended.
• However, LMWH therapy is recommended for women who develop severe ovarian hyperstimulation syndrome.
• LMWH should be discontinued at least 24 hours before the induction of labor or a planned cesarean delivery.
• For women undergoing cesarean section and who have additional risk factors for developing VTE the prophylactic use of LMWH may be considered
• For women who require long-term anticoagulation with warfarin and who are considering pregnancy, LMWH substitution should be done prior to conception when possible.
• When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), the burden of therapy, and maternal preference should be considered.

Nadroparin use during breastfeeding:

• Small amounts of low molecular weight heparins (LMWHs) may be secreted in breast milk; however because they have a low oral bioavailability.
• LMWHs are unlikely to cause adverse events in a breastfeeding infant.
• Breastfeeding is not recommended by the manufacturer
• However, antithrombotic guidelines note the use of LMWH may be continued in breastfeeding women.

Nadroparin (Fraxiparine) Dose in Kidney Disease:

• CrCl ≥50 mL/minute:

  • Dosage adjustment not necessary.

• CrCl ≥30 to <50 mL/minute:

  • Decrease dose by 25% to 33%.
  • Some have suggested that no dose adjustment is needed when used for prophylaxis
  • One small clinical trial found no change in peak anti-Xa activity after five days of nadroparin at prophylactic doses (Atiq 2015).

• CrCl <30 mL/minute:

  • Prophylaxis: Reduce dose by 25% to 33%.
  • Treatment: Use is contraindicated.

• Hemodialysis:

  • Not dialyzable.

Nadroparin (Fraxiparine) Dose in Liver disease:

In the manufacturer's labeling no dosage adjustments have been provided (has not been studied).

Side effects of Nadroparin (Fraxiparine):

As with all anticoagulants, bleeding is the major adverse effect of nadroparin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables.

• Cardiovascular:

  • Arterial thrombosis
  • Thromboembolism
  • Venous thrombosis

• Dermatologic:

  • Skin rash

• Endocrine & metabolic:

  • Calcinosis
  • Hypoaldosteronism (causing hyperkalemia and/or hyponatremia)

• Hematological & oncologic:

  • Hemorrhage
  • Thrombocythemia
  • Thrombocytopenia

• Hepatic:

  • Increased serum ALT
  • Increased serum AST

• Hypersensitivity:

  • Hypersensitivity reaction

• Local:

  • Hematoma at the injection site
  • Pain at the injection site

• Neuromuscular & skeletal:

  • Osteopenia

Contraindications to Nadroparin (Fraxiparine):

• Hypersensitivity to nadroparin, any component of the formulation, or to other low molecular weight heparins and/or heparin
• Acute infective endocarditis
• Active bleeding or increased risk of hemorrhage (hemostasis disorder
• The history of confirmed or suspected immunologically mediated heparin-induced thrombocytopenia (HIT) (delayed-onset severe thrombocytopenia) or positive in vitro test for antiplatelet antibodies in the presence of nadroparin
• Major blood clotting disorders
• Hemorrhagic tendency or other conditions involving increase risk of bleeding
• Organic lesions likely to bleed (active peptic ulceration)
• Hemorrhagic cerebrovascular event
• Severe uncontrolled hypertension
• Diabetic or hemorrhagic retinopathy
• Injuries to or operations on the CNS, eyes, or ears
• Severe renal insufficiency (creatinine clearance <30 mL/minute when used for treatment)
• Concomitant use of spinal/epidural anesthesia with repeated high-dose nadroparin (eg, 171 units/kg/day)

Note:

• The use of nadroparin in patients with current HIT or HIT with thrombosis is not recommended & considered contraindicated due to high cross-reactivity to heparin-platelet factor-4 antibody.

Warnings and Precautions

• Bleeding:

  • Bleeding may occur at any site during therapy.
  • Monitor patients closely for signs or symptoms of bleeding.
  • Certain patients are at increased risk of bleeding.
  • Risk factors include:
    • Bacterial endocarditis
    • Congenital or acquired bleeding disorders
    • Active ulcerative or angiodysplasia GI diseases
    • Severe uncontrolled hypertension
    • Hemorrhagic stroke
    • Use shortly after brain, spinal, or ophthalmology surgery
    • In patients treated concomitantly with other drugs known to cause bleeding (eg, platelet inhibitors)
    • Recent GI bleeding or ulceration
    • Vascular disorder of the chorio-retina
    • Thrombocytopenia or platelet defects
    • Severe liver disease
    • Hypertensive or diabetic retinopathy
    • In patients undergoing invasive procedures
    • In the elderly.
      • Discontinue if bleeding occurs.
      • Protamine infusion may be necessary for serious bleeding (consult Protamine monograph for dosing recommendations).

• Cutaneous necrosis:

  • Cutaneous necrosis preceded by purpura or infiltrated or painful erythematous blotches has been reported rarely
  • Discontinue treatment immediately if suspected.

• Hyperkalemia:

  • Monitor for hyperkalemia
  • It can cause hyperkalemia possibly by suppressing aldosterone production.
  • Most commonly occurs in patients with risk factors for the development of hyperkalemia (eg, renal dysfunction, concomitant use of potassium-sparing diuretics or potassium supplements, and hematoma in body tissues).

• Thrombocytopenia:

  • Cases of thrombocytopenia including thrombocytopenia with thrombosis have occurred.
  • Use cautiously in patients with a history of thrombocytopenia (drug-induced or congenital) or platelet defects; monitor platelet counts closely.
  • Contraindicated for use in patients with a history of confirmed or suspected heparin-induced thrombocytopenia (HIT) or positive in vitro test for antiplatelet antibodies in the presence of nadroparin.
  • If platelets are less than 100,000/mm³ and/or thrombosis develops.
  • Discontinue therapy and consider alternative treatment

• Cardiovascular disease:

  • Use cautiously in patients with severe arterial hypertension.

• GI disease:

  • Use cautiously in patients with a history of GI ulceration
  • Contraindicated in patients with active peptic ulceration.

• Hepatic impairment:

  • Use cautiously in patients with hepatic impairment (has not been studied);
  • Patients with hepatic failure are at an increased risk of bleeding.

• Prosthetic heart valves:

  • Prosthetic valve thrombosis has been reported in patients receiving thromboprophylaxis therapy with LMWHs.
  • Pregnant women may be at increased risk.

• Renal impairment:

  • Use cautiously in patients with renal impairment
  • It is primarily excreted via the kidneys.
  • Dose reductions may be required.
  • Contraindicated in severe renal impairment when treating thromboembolic disorders, unstable angina, and NSTEMI

Nadroparin (United States: Not available): Drug Interaction

Monitoring parameters:

• Platelet counts (at baseline and then twice weekly during therapy),
• Bleeding complications including stool occult blood tests, hemoglobin, anti-factor Xa levels (recommended to obtain levels four hours postdose)
• Renal and hepatic function
• Potassium in patients at risk for hyperkalemia
• Signs/symptoms of neurological impairment

When used for anticoagulation during hemodialysis, carefully monitor patients for signs of bleeding or clotting in the dialysis session.

How to administer Nadroparin (Fraxiparine)?

SubQ:

• Administer by SubQ injection into the anterolateral abdominal wall with subsequent doses to be administered alternately on the right and left side of the abdominal wall.
• The thigh may also be used as an alternative site.
• Do not administer intramuscularly.

Intravenous injection:

• It may be administered Intravenous only as an initial bolus dose for acute coronary syndromes (unstable angina and NSTEMI [ie, non-Q-wave myocardial infarction]).

Hemodialysis:

• At the start of the dialysis session inject into the arterial line.

Mechanism of action of Nadroparin (Fraxiparine):

• Nadroparin is low molecular weight heparin (LMWH) (average molecular weight is ~4,300 daltons, distributed as 2,000 to 8,000 daltons [75% to 85%]) that binds antithrombin III, enhancing the inhibition of several clotting factors, particularly factor Xa.
• Nadroparin anti-Xa activity (85 to 110 units/mg) is greater than anti-IIa activity (~27 units/mg) and it has a higher ratio of anti-factor Xa to anti-factor IIa activity compared to unfractionated heparin.
• LMWHs have a small effect on the activated partial thromboplastin time.

Note:

• Values reflective of anti-Xa activity.

Duration:

• Anti-Xa activity: ≥18 hours

Metabolism:

• Hepatic

Bioavailability:

• SubQ: ~98%

Half-life elimination:

• ~3.5 hours (prolonged in renal impairment)

Time to peak serum concentrations:

• SubQ: three to six hours

Excretion:

• Urine (primarily)

International Brands of Nadroparin:

• Fraxiparine
• Fraxiparine Forte
• Cardioparin
• Fraxiparin
• Fraxiparina
• Fraxiparine TX
• Fraxodi

Nadroparin Brand Names in Pakistan: