Active ingredients: Nadroparin (Calcium Nadroparin)
FRAXIPARINA 2.850 I.U. antiXa / 0.3 ml solution for injection
FRAXIPARINA 3,800 I.U. antiXa / 0.4 ml solution for injection
FRAXIPARINA 5,700 I.U. antiXa / 0.6 ml solution for injection
FRAXIPARINA 7,600 I.U. antiXa / 0.8 ml solution for injection
FRAXIPARINA 9.500 I.U. antiXa / 1 ml solution for injection
Why is Fraxiparin used? What is it for?
Fraxiparin contains the active substance nadroparin calcium, an antithrombotic derived from heparin used to prevent blood clots.
Fraxiparin is used:
- In the prevention of deep vein thrombosis (DVT) in general surgery and in orthopedic surgery. It is therefore used to prevent the formation of clots in the veins of the legs in case of impossibility or reduced possibility of movement following major surgery.
- In the treatment of deep vein thrombosis.
- In the prevention of clot formation during hemodialysis which serves to purify the blood in patients suffering from renal insufficiency
- In the treatment of particular forms of heart attack (unstable angina and non-Q myocardial infarction).
Talk to your doctor if you don't feel better or if you feel worse.
Contraindications When Fraxiparin should not be used
Do not use FRAXIPARINE
- if you are allergic to calcium nadroparin or any of the other ingredients of this medicine
- if you have a history of thrombocytopenia (low number of platelets, the cells responsible for blood clotting)
- if you are at an increased risk of bleeding related to bleeding disorders, with the exception of disseminated intravascular coagulation (a severe syndrome that leads to blood clotting in many blood vessels) not induced by heparin.
- if you have lesions at risk of bleeding (such as active peptic ulcer - stomach wall ulcer)
- if you suffer (or have suffered) from retinopathies (diseases of the retina, the membrane that covers the inner surface of the eye)
- if you suffer (or have suffered) from bleeding syndrome.
- if you have (or have suffered) from brain haemorrhages (brain haemorrhages)
- if you have (or have suffered) from an "infection of the inner lining of the heart (acute infective endocarditis)
- if you have severe renal insufficiency and are being treated for deep vein thrombosis, unstable angina and non-Q myocardial infarction.
- if you have severe kidney or pancreatic disease,
- if you have very high blood pressure (severe arterial hypertension)
- if you have recently been operated on for a head injury (surgically treated head injury)
- in case of loco-regional anesthesia for surgical procedures.
Precautions for use What you need to know before taking Fraxiparin
Talk to your doctor or pharmacist before using Fraxiparin.
You may develop heparin-induced thrombocytopenia (low platelet count), therefore your platelet count should be monitored throughout the course of nadroparin treatment.
There have been rare reports of thrombocytopenia, occasionally severe, which may be associated with arterial or venous thrombosis. This diagnosis should be considered in the following situations:
- thrombocytopenia
- any significant reduction in the level of platelets
- worsening of the initial thrombosis during therapy
- thrombosis that occurs during treatment
- disseminated intravascular coagulation
In such cases, nadroparin treatment should be discontinued.
In case of thrombocytopenia due to treatment with heparin (both standard and low molecular weight) your doctor may consider:
- if necessary, treatment with nadroparin.
- replacement with an anti-thrombotic of a different class
- if this is not possible, but the administration of heparin is still necessary, the replacement with another "low molecular weight heparin
In such cases, your doctor will need to monitor the platelet count at least daily and if thrombocytopenia occurs, the treatment should be stopped immediately (see "Do not use FRAXIPARINE").
Nadroparin should be used with caution in the following situations, which may be associated with an increased risk of bleeding:
- liver malfunction (liver failure)
- very high blood pressure (severe arterial hypertension)
- history of stomach ulcer (peptic ulcer) or other organic lesions at risk of bleeding
- vascular disease of chorioretin (a part of the eye with many blood vessels)
- during the postoperative period following brain surgery, vertebral or eye surgery, and in head injuries.
Pay particular attention:
- If you have impaired kidney function: you have an increased risk of bleeding and should be treated with caution
- If you are elderly: your doctor will need to check your kidney function before starting treatment (see "Do not use Fraxiparin").
- If you have high levels of potassium in your blood or if you are at risk of increased potassium levels, for example if you have diabetes mellitus, chronic kidney failure, pre-existing metabolic acidosis (disturbances in the concentration of gases and salts in the blood) or if you take drugs that can increase potassium levels in your blood (for example, ACE inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs)), heparin can suppress the production of aldosterone (a hormone that regulates the concentration of salts in the blood) with resulting in increased blood potassium levels This risk appears to increase in relation to the duration of therapy, but is generally reversible.
- If you are undergoing spinal or epidural anesthesia, the use of low molecular weight heparin may rarely be associated with hematomas, which can lead to prolonged or permanent paralysis of the lower limbs. You will therefore need to be monitored frequently for signs and symptoms of neurological changes. , such as back pain, sensory and motor deficits (numbness and weakness in the lower limbs), bowel and / or bladder dysfunction. You should inform a doctor or healthcare professional immediately if any of the above symptoms occur. The risk of spinal hematomas / epidural is augmented by catheters placed in the spinal cord (epidural catheter) or by concomitant use of other drugs that can affect clotting, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors or other anticoagulants. The risk is also increased by trauma or repeated lumbar punctures.
- if you notice signs such as dark red color (cutaneous purpura) or infiltrated or painful erythematous plaques, with or without general symptoms, as these may be associated with skin anecrosis (i.e. death of skin tissues) which has been reported very rarely. In such cases, doctor will stop treatment immediately.
Latex allergy
The protective cap of the needle of the pre-filled syringe may contain latex rubber. It may cause severe allergic reactions in those sensitive to latex.
Children and adolescents
Nadroparin is not recommended for children and adolescents under the age of 18.
Interactions Which drugs or foods can modify the effect of Fraxiparin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Nadroparin should be administered with caution if you are taking:
- oral anti-coagulants, as concomitant administration can increase the anticoagulant effect
- (gluco-) systemic corticosteroids (cortisone and the like), as concomitant administration may increase the risk of bleeding
- dextrans (substances used to increase blood volume) as concomitant administration may increase the risk of bleeding
- In case of concomitant administration of ascorbic acid (vitamin C), antihistamines, digitalis, penicillins IV, tetracyclines or phenothiazines, as it is possible to administer concurrently, the activity of the drug may be decreased.
Fraxiparin is not recommended if you are taking the following medicines as the risk of bleeding increases in these cases:
- Acetylsalicylic acid and other salicylates, non-steroidal anti-inflammatory drugs - NSAIDs (by general route). Use other substances for a pain relieving or antipyretic effect.
- Ticlopidine (oral anticoagulant) - Other antiplatelet agents (clopidogrel, dipyridamole, sulfinpyrazone, etc.)
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Pregnancy
The use of nadroparin in pregnancy is not recommended unless the therapeutic benefits outweigh the possible risks.
Feeding time
Information on the excretion of nadroparin in breast milk is limited. As a precaution, nursing mothers receiving nadroparin should be advised not to breastfeed.
Fertility
There are no studies on the effect of nadroparin on fertility.
Driving and using machines
No studies on the ability to drive and use machines have been performed.
Dosage and method of use How to use Fraxiparin: Dosage
Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Do not mix calcium nadroparin with other preparations.
Pay particular attention to the dosing instructions, specific to different brands of low molecular weight heparin, as different measurement systems are used for each low molecular weight heparin to express the doses (Units or mg).
Therefore nadroparin should not be used interchangeably with other low molecular weight heparins in the course of treatment.
Nadroparin should not be administered intramuscularly.
Administration of nadroparin in the period of time close to a spinal / epidural anesthesia or a lumbar puncture should follow specific recommendations (see "Warnings and precautions").
You should monitor your platelet count throughout the course of nadroparin treatment (see "Warnings and precautions").
Subcutaneous injection technique
When adroparin is administered subcutaneously, injection should be given in the anterolateral or posterolateral side of the abdominal wall, alternating between the right and left sides. The thigh may be an alternative site.
To avoid leakage of solution when using pre-filled syringes, you should not expel the air bubble from the syringe before injecting.
The needle must be introduced entirely, perpendicularly (ie forming an angle of 90 degrees with the abdomen) and not tangentially, in the thickness of a skin fold made between the thumb and forefinger of the operator.
The fold must be maintained for the duration of the injection. At the end of the injection, do not rub the skin, but apply light pressure on the site.
In the case of a dosage adapted to its weight, the volume to be administered is adjusted by bringing the piston to the desired notch, keeping the syringe in a vertical position.
The syringes are for single use only and any unused contents of each syringe should be discarded. Solutions should not be mixed with other preparations or re-administered.
Prevention of deep vein thrombosis
Subcutaneous administration
In general surgery: the recommended dose is one subcutaneous injection 2-4 hours before surgery. Subsequently every 24 hours for at least 7 days; in all cases, prophylaxis must continue throughout the risk period and at least until walking starts again.
In orthopedic surgery: the recommended dose is one preoperative injection 12 hours before surgery, one postoperative 12 hours after the end of surgery, then one daily injection. The duration of the treatment is at least 10 days; in all cases, prophylaxis should be continued throughout the risk period and at least until walking starts again.
Treatment of deep vein thrombosis
Subcutaneous administration: the recommended dose is one injection every 12 hours
If there are no contraindications, start oral anticoagulant therapy as soon as possible.
You should monitor your platelet count throughout the course of nadroparin treatment (see "Warnings and precautions").
Prevention of coagulation during hemodialysis
Intravascular administration: if there is no risk of bleeding and for a session lasting less than or equal to 4 hours, an injection of a single dose must be given at the beginning of the session, in the arterial access, evaluated according to its weight.
If you have an increased risk of bleeding, dialysis sessions can be performed using a dose reduced by half.
For sessions longer than 4 hours, a further reduced dose can be administered. For subsequent dialysis sessions, if necessary, the dose can be adjusted based on the effect observed initially.
He must be carefully monitored during the dialysis session for any signs of bleeding or clotting in the dialysis circuit.
Treatment of unstable angina and non-Q myocardial infarction
Subcutaneous administration
The recommended dose of nadroparin, administered subcutaneously, is twice daily (every 12 hours). The duration of treatment is generally 6 days.
Use in children and adolescents
Nadroparin is not recommended in children and adolescents as there are insufficient safety and efficacy data to establish the dose in patients below 18 years of age.
Senior citizens
No dose adjustment is necessary if you are elderly unless renal function is impaired. Your doctor will check your kidney function before starting treatment (see "Renal impairment" below).
Kidney failure
Prevention of deep vein thrombosis
No dose reduction is required if you have mild renal insufficiency. If you have moderate or severe renal insufficiency you have an increased risk of thromboembolism and haemorrhage. Where the physician deems a dose reduction appropriate, taking into account individual haemorrhagic and thromboembolic risk factors, if you have moderate or severe renal insufficiency the dose should be reduced variably (see "Warnings and precautions").
Fraxiparin is contraindicated if you have severe renal insufficiency.
Treatment of deep vein thrombosis, unstable angina and non-Q myocardial infarction.
If you have mild renal insufficiency and are taking nadroparin to treat these conditions, a dose reduction is not necessary.
If you have moderate or severe renal insufficiency you have an increased risk of thromboembolism and haemorrhage.
If the physician judges a dose reduction appropriate, taking into account individual haemorrhagic and thromboembolic risk factors, if you have moderate or severe renal insufficiency, the dose should be reduced variably (see "Warnings and precautions").
Nadroparin is contraindicated in patients with severe renal insufficiency
Hepatic impairment No studies have been conducted in patients with hepatic impairment.
Overdose What to do if you have taken too much Fraxiparin
If you accidentally take an overdose of Fraxiparin, notify your doctor immediately or go to the nearest hospital.
The most obvious manifestation of overdose, both subcutaneously and intravenously, is haemorrhage. In this case the doctor will have to perform a platelet count to measure the other coagulation parameters.
Minor bleeding rarely requires specific therapy and it is usually sufficient to reduce or delay subsequent doses of nadroparin.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
If you stop taking Fraxiparin
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Fraxiparin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Side effects are listed below in order of frequency of occurrence:
Very common (may affect more than 1 in 10 people)
- Bleeding at various sites (including cases of spinal hematoma), more frequent in patients with other risk factors (see "Do not use Fraxiparin" and "Warnings and precautions").
- Injection hematoma. In some cases, the appearance of fixed nodules may be noted. These nodules generally disappear after a few days.
Common (may affect up to 1 in 10 people)
- Increase in transaminases (enzymes produced by the liver), usually transient
- Injection site reaction
Rare (may affect up to 1 in 1,000 people)
- Thrombocytopenia, i.e. reduction in the number of platelets in the blood (including that induced by heparin), thrombocytosis (increase in the number of platelets in the blood).
- Rash, hives, erythema, itching.
- Calcinosis (deposition of calcium salts) at the injection site. Calcinosis is more common in patients with abnormal calcium phosphate production, as well as in some cases of chronic renal failure.
Very rare (may affect up to 1 in 10,000 people)
- Eosinophilia, i.e. an increase in the number of a type of white blood cell in the blood which is reversible upon discontinuation of treatment.
- Hypersensitivity reactions (including angioedema and skin reactions), anaphylactoid reaction.
- reversible increase in blood potassium concentration particularly in patients at risk
- Priapism (abnormal, prolonged and painful erections).
- Skin necrosis (death of skin tissues), usually at the injection site
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. / responsible.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry date refers to the last day of that month. The expiry date indicated refers to the unopened, correctly stored product.
Do not use this medicine if you notice any particulate matter (i.e. solid material in a liquid solution) or a change in color of the nadroparin solution for injection. If you visually notice any change, the solution should be discarded.
This medicine does not require any special storage conditions.
Do not freeze. Do not refrigerate as cold injections can be painful.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What FRAXIPARINE contains
The active ingredient is calcium nadroparin (I.U.antiXa). 1 pre-filled syringe contains:
- 0.3 ml of FRAXIPARINA 2.850 I.U. antiXa;
- 0.4 ml of FRAXIPARINA 3.800 I.U. antiXa;
- 0.6 ml of FRAXIPARINA 5.700U.I. antiXa;
- 0.8 ml of FRAXIPARINA 7.600U.I. antiXa;
- 1 ml of FRAXIPARINA 9.500U.I. antiXa.
The other ingredients are: calcium hydroxide solution or diluted hydrochloric acid - water for injections.
Description of what Fraxiparin looks like and contents of the pack
Solution for injection for subcutaneous use and for hemodialysis
- 6 pre-filled graduated syringes ready for use of 0.3 ml (2,850 I.U.antiXa)
- 6 pre-filled graduated syringes ready for use of 0.4 ml (3,800 I.U.antiXa)
- 10 pre-filled graduated syringes ready for use of 0.6 ml (5,700 I.U.antiXa)
- 10 pre-filled graduated syringes ready for use of 0.8 ml (7.600 I.U.antiXa)
- 10 pre-filled graduated syringes ready for use of 1 ml (9,500 I.U.antiXa)
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
FRAXIPARINA
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection for subcutaneous use and for hemodialysis.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
- Prophylaxis of deep vein thrombosis (DVT) in general surgery and orthopedic surgery.
- Treatment of deep vein thrombosis.
- Prevention of coagulation during hemodialysis.
- Treatment of unstable angina and non-Q myocardial infarction.
04.2 Posology and method of administration
Dosage
Particular attention should be paid to the dosing instructions, specific for different brands of low molecular weight heparin, as different measurement systems are used for each low molecular weight heparin to express the doses (Units or mg).
Therefore nadroparin should not be used interchangeably with other low molecular weight heparins in the course of treatment.
Prophylaxis of deep vein thrombosis
Subcutaneous administration
In general surgery:
A subcutaneous injection of 0.3 ml (2,850 IU antiXa) 2-4 hours before surgery. Subsequently every 24 hours for at least 7 days; in all cases, prophylaxis must be continued for the entire risk period and at least until the patient resumes ambulation.
In orthopedic surgery:
The dosage, which consists of a "single daily subcutaneous injection, must be adjusted according to the patient's weight, according to the table below.
A "preoperative injection of 38 IU antiXa / kg 12 hours before the" surgery, a postoperative 12 hours after the end of the "surgery, then a" daily injection up to the 3rd postoperative day included; 57 I.U. antiXa / kg / day starting from the 4th postoperative day.
The duration of the treatment is at least 10 days; in all cases, prophylaxis must be continued for the entire risk period and at least until the patient resumes walking.
By way of example and depending on the weight of the patient, the posologies to be administered are as follows:
0.1 ml of nadroparin contain 950 I.U. antiXa
Treatment of deep vein thrombosis
Subcutaneous administration
One injection every 12 hours for 10 days at a dose of approximately 92.7 IU antiXa / kg.
By way of example and depending on the weight of the patient, the posologies to be administered are as follows:
If there are no contraindications, start oral anticoagulant therapy as soon as possible.
Nadroparin treatment should not be stopped until the required International Normalized Ratio (INR) has been reached.
Platelet counts should be monitored throughout the course of nadroparin treatment (see section 4.4 Special warnings and precautions for use).
Prevention of coagulation during hemodialysis
Intravascular administration
In the prevention of coagulation in the course of extracorporeal circulation during hemodialysis.
In those patients who do not have a bleeding risk and for a session lasting less than or equal to 4 hours, at the beginning of the session, practice an injection, in the arterial access, of a single dose, evaluated according to the patient's weight, of the order of 64.6 IU antiXa / kg.
By way of example and depending on the patient's weight:
If necessary, the dose will be adjusted on a case-by-case basis according to the patient and the technical conditions of dialysis.
For subjects with an increased risk of bleeding, dialysis sessions can be performed using a dose reduced by half.
For sessions lasting more than 4 hours it is possible to administer a further reduced dose.
For subsequent dialysis sessions, if necessary, the dose can be adjusted based on the effect observed initially.
Patients should be carefully monitored during the dialysis session for any signs of bleeding or clotting in the dialysis circuit.
Treatment of unstable angina and non-Q myocardial infarction
Subcutaneous administration
Nadroparin should be administered, subcutaneously, twice daily (every 12 hours). The duration of treatment is generally 6 days. In clinical studies in patients with unstable angina and non-Q myocardial infarction, nadroparin was administered in combination with acetylsalicylic acid at a maximum dose of 325 mg per day.
The initial dose should be administered as an intravenous bolus of 86 I.U. antiXa / kg, followed by subcutaneous injections of 86 I.U. antiXa / kg.
The dose should be based on the patient's weight.
By way of example and depending on the patient's weight, the dosages to be administered are as follows:
Pediatric population
Nadroparin is not recommended in children and adolescents as there are insufficient safety and efficacy data to establish the dosage in patients below 18 years of age.
Senior citizens
No dosage adjustment is necessary in the elderly unless renal function is impaired.It is recommended that renal function be checked before starting treatment (see Renal impairment and section 5.2 Pharmacokinetic properties below).
Kidney failure
Prophylaxis of deep vein thrombosis
No dose reduction is required in patients with mild renal impairment (creatinine clearance greater than or equal to 50 ml / min). "Both moderate and severe renal insufficiency is associated with" increased nadroparin exposure. These patients have an increased risk of thromboembolism and haemorrhage. In patients with moderate renal insufficiency (creatinine clearance greater than or equal to 30 ml / min and less than 50 ml / min) the dose should be considered appropriate by the physician, taking into account individual haemorrhagic and thromboembolic risk factors. be reduced by varying degrees from 25% to 33% (see sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties).
The dose should be reduced from 25% to 33% in patients with severe renal impairment (creatinine clearance less than 30 ml / min) (see sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties).
Treatment of deep vein thrombosis, unstable angina and non-Q myocardial infarction
In patients with mild renal impairment (creatinine clearance ≥50 mL / min) receiving nadroparin for the treatment of these conditions, no dose reduction is required.
"Both moderate and severe renal insufficiency is associated with" increased nadroparin exposure. These patients have an increased risk of thromboembolism and haemorrhage.
In patients with moderate renal impairment (creatinine clearance greater than or equal to 30 ml / min and less than 50 ml / min) the dose should be considered appropriate by the physician, taking into account individual haemorrhagic and thromboembolic risk factors. be reduced by varying degrees from 25% to 33% (see sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties).
Nadroparin is contraindicated in patients with severe renal impairment (see sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties).
Hepatic insufficiency
No studies have been conducted in patients with hepatic insufficiency.
Method of administration
Nadroparin should not be administered intramuscularly.
Administration of nadroparin close to spinal / epidural anesthesia or lumbar spinal injection should follow specific recommendations (see section 4.4 Special warnings and precautions for use).
Subcutaneous injection technique
When nadroparin is administered subcutaneously, injection should be given into the anterolateral or posterolateral abdominal girdle, alternating left and right. The thigh may be an alternate site.
To avoid leakage of solution when using pre-filled syringes, you should not expel the air bubble from the syringe before injecting.
The needle must be introduced entirely, perpendicularly and not tangentially, into the thickness of a skin fold made between the thumb and the index finger of the operator.
The fold must be maintained for the entire duration of the injection. At the end of the injection, do not rub the skin, but apply moderate pressure on the site.
In the case of a dosage adapted to the weight of the patient, the volume to be administered is adjusted by bringing the piston to the desired notch while holding the syringe in a vertical position.
04.3 Contraindications
Nadroparin is contraindicated in cases of:
- hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- history of thrombocytopenia with nadroparin (see also section 4.4 Special warnings and precautions for use)
- active bleeding or increased bleeding risk related to haemostasis disorders, with the exception of disseminated intravascular coagulation not induced by heparin
- organic lesions at risk of bleeding (peptic ulcer in active phase, retinopathies, haemorrhagic syndrome)
- haemorrhagic cerebrovascular accidents
- acute infective endocarditis
- severe renal insufficiency (clearance of creatinine deep vein thrombosis, unstable angina and non-Q myocardial infarction
- severe nephropathies and pancreopathies, severe arterial hypertension, severe cranioencephalic trauma in the postoperative period
- The multidose bottle contains benzyl alcohol and therefore should not be used in children under the age of three
- loco-regional anesthesia for elective surgical procedures is contraindicated in those patients receiving low molecular weight heparin for therapeutic use.
04.4 Special warnings and appropriate precautions for use
Thrombocytopenia induced by heparin
Due to the possibility of heparin-induced thrombocytopenia, platelet counts should be monitored throughout the course of nadroparin treatment.
There have been rare reports of thrombocytopenia, occasionally severe, which may be associated with arterial or venous thrombosis. This diagnosis should be considered in the following situations:
- thrombocytopenia
- any significant reduction in platelet level (30-50% compared to baseline)
- worsening of the initial thrombosis during therapy
- thrombosis which occurs during treatment
- disseminated intravascular coagulation.
In such cases, nadroparin treatment should be discontinued.
These effects are probably of an immune-allergic nature and, in the case of a first treatment, have been reported mainly between the 5th and 21st day of therapy, but can also appear much earlier in the case of a history of thrombocytopenia induced by heparin.
In the event of a history of thrombocytopenia occurring with treatment with heparin (both standard and low molecular weight), treatment with nadroparin may be considered if necessary. In such cases, careful clinical monitoring and verification of platelet counts should be done at least once a day. If thrombocytopenia occurs, treatment should be stopped immediately.
When thrombocytopenia occurs with the use of heparin (standard or low molecular weight), replacement with an anti-thrombotic of a different class should be considered.
If this is not possible, but heparin administration is still required, substitution with another low molecular weight heparin may be considered. In such cases, platelet count monitoring should be performed at least daily and treatment should be performed. be discontinued as soon as possible, as cases of initial thrombocytopenia which continued after replacement have been reported (see section 4.3 Contraindications).
Platelet aggregation test in vitro they are of limited value in the diagnosis of heparin-induced thrombocytopenia.
Nadroparin should be administered with caution in the following situations, which may be associated with an increased risk of bleeding:
- hepatic insufficiency
- severe arterial hypertension
- clinical history of peptic ulcer or other organic lesions at risk of bleeding
- vascular diseases of chorioretina
- during the postoperative period following brain, spinal cord or eye surgery and in head injuries
Kidney failure
Nadroparin is known to be primarily excreted via the kidneys, resulting in increased nadroparin exposure for patients with renal insufficiency (see section 5.2 Pharmacokinetic properties - Renal insufficiency). Patients with impaired renal function have an increased risk of bleeding and should be treated with caution.
Any dose reduction in patients with creatinine clearance between 30ml / min and 50ml / min should be based on the clinician's clinical assessment of the individual bleeding risk versus thromboembolism risk (see section 4.2 Posology and method of administration).
Senior citizens
It is recommended to check renal function before starting treatment (see section 4.3 Contraindications).
Hyperkalemia
Heparin may suppress adrenal secretion of aldosterone resulting in hyperkalaemia, particularly in those patients with elevated plasma potassium levels, or at risk of increased plasma potassium levels, such as patients with diabetes mellitus, chronic renal failure, pre-metabolic acidosis. -existing or taking drugs that can cause hyperkalaemia (eg angiotensin converting enzyme inhibitors (ACE inhibitors), non-steroidal anti-inflammatory drugs (NSAIDs)).
The risk of hyperkalaemia appears to increase in relation to the duration of therapy, but is generally reversible.
In patients at risk, plasma potassium should be monitored.
Spinal / epidural anesthesia, lumbar puncture and concomitant medications
In patients undergoing spinal or epidural anesthesia, the use of low molecular weight heparin may rarely be associated with hematomas, which can lead to prolonged or permanent paralysis of the lower limbs.
The risk of spinal / epidural hematomas is increased by the use of indwelling epidural catheters or by the concomitant use of other drugs that can affect haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors or others. anticoagulants. The risk is also increased by trauma or by repeated epidural or lumbar punctures.
Therefore, the concomitant use of a neuraxial block and anti-coagulation therapy must be decided after carefully establishing the individual benefit / risk balance in the following situations:
- in patients already treated with anti-coagulants, the benefits of a neuraxial block must be carefully weighed against the risks;
- in patients in whom elective surgery with neuraxial block is planned, the benefits of anticoagulant therapy must be carefully weighed against the risks.
In the case of patients undergoing lumbar spinal puncture, spinal anesthesia or epidural anesthesia, 12 hours must elapse between the injection of nadroparin in prophylactic doses and the insertion or removal of the catheter or spinal / epidural needle and at least 24 hours in the case of nadroparin injection at treatment doses taking into account product characteristics and patient profile.
For patients with renal insufficiency, longer time intervals should be considered. The next dose should not be given until at least 4 hours have elapsed.
Re-administration of nadroparin should be delayed until the surgical procedure has been completed.
Patients should be monitored frequently for signs and symptoms of neurological changes, such as lower back pain, sensory and motor deficits in the lower limbs (numbness and weakness), bowel and / or bladder dysfunction. If neurological impairment is noted, urgent treatment is required. Healthcare professionals should be prepared to detect such signs and symptoms. Patients should be advised to notify a physician or healthcare professional immediately if any of the above symptoms occur. .
If signs or symptoms of epidural or spinal hematoma are suspected, a diagnosis and treatment that includes decompression of the spinal cord should be made urgently.
If significant or obvious bleeding has occurred during placement of the epidural catheter, a careful benefit / risk assessment should be made before initiating / resuming heparin therapy.
Skin necrosis
Skin necrosis has been reported very rarely. It is preceded by infiltrated or painful purpura or erythematous plaques, with or without general symptoms. In such cases, the treatment must be stopped immediately.
Latex allergy
The needle cap of the pre-filled syringe may contain natural latex rubber which may cause allergic reactions in latex sensitive individuals.
04.5 Interactions with other medicinal products and other forms of interaction
Nadroparin should be administered with caution in patients receiving oral anti-coagulant agents, systemic (gluco-) corticosteroids and dextrans. When initiating oral anticoagulant therapy in patients receiving nadroparin, nadroparin treatment should be continued until the International Normalized Ratio (INR) has stabilized at the required value.
Salicylates, non-steroidal anti-inflammatory drugs and anti-platelet aggregating drugs
In the prophylaxis or treatment of venous thromboembolic disorders and in the prevention of clotting during hemodialysis, the concomitant use of aspirin, other salicylates, NSAIDs and antiplatelet agents is not recommended, as these drugs may increase the risk of hemorrhage. When such combinations cannot be avoided, careful monitoring of clinical and biological parameters is recommended.
In clinical trials for the treatment of unstable angina and non-Q myocardial infarction, nadroparin was administered in combination with aspirin up to a maximum dose of 325 mg per day of acetylsalicylic acid (see sections 4.2 Posology and method of administration and 4.4 Special warnings and precautions for use).
Associations not recommended
- Acetylsalicylic acid and other salicylates (generally)
Increased risk of bleeding (inhibition of platelet function and aggression of the gastroduodenal mucosa by salicylates).
Use other substances for an analgesic or antipyretic effect.
In the case of treatment of unstable angina and non-Q myocardial infarction, nadroparin should be administered in combination with acetylsalicylic acid at a maximum dose of 325 mg / day (see sections 4.2 Posology and method of administration and 4.4 Special warnings and precautions of use).
- NSAIDs (generally)
Increased risk of bleeding (inhibition of platelet function and aggression of the gastroduodenal mucosa by non-steroidal anti-inflammatory drugs).
If the association cannot be avoided, institute careful clinical and biological surveillance.
- Ticlopidine: increased risk of bleeding (inhibition of platelet function by ticlopidine).
The association with high doses of heparin is not recommended: the association with low doses of heparin (preventive heparinotherapy) requires careful clinical and biological surveillance.
- Other antiplatelet agents (clopidogrel, dipyridamole, sulfinpyrazone, etc.): increased risk of bleeding (inhibition of platelet function).
Associations requiring precautions for use:
- Oral anticoagulants
Enhancement of anticoagulant action. Heparin distorts the prothrombin rate.
When replacing heparin with oral anticoagulants:
- reinforce clinical and biological surveillance (Quick time expressed in INR).
- to check the effect of oral anticoagulants, take the sample before heparin administration, if this is discontinuous or, preferably, use a reagent that is not sensitive to heparin. Due to the latency time required for the oral anticoagulant to be fully effective, heparin treatment should be continued until the INR has stabilized in the therapeutic range (between 2 and 3).
- Glucocorticoids (general route)
Worsening of the haemorrhagic risk typical of glucocorticoid therapy (gastric mucosa, vascular fragility), at high doses or in prolonged treatment for more than ten days.
The association must be justified; enhance clinical surveillance.
- Dextran (injecting)
Increased risk of bleeding (inhibition of platelet function).
Adjust the dosage of heparin so as not to exceed a hypocoagulability greater than 1.5 times the reference value, during the combination and after the suspension of dextran.
- In case of simultaneous administration of ascorbic acid, antihistamines, digitalis, IV penicillins, tetracyclines or phenothiazines, an inhibition of the activity of the drug may occur.
04.6 Pregnancy and breastfeeding
Pregnancy
Studies in animals have not shown any teratogenic or foetotoxic activity. However, there are only limited clinical data regarding the passage of nadroparin through the placenta in pregnant women. Therefore the use of nadroparin in pregnancy is not recommended, unless the therapeutic benefits outweigh the possible risks.
Feeding time
Information on the excretion of nadroparin in breast milk is limited. Current knowledge indicates that, due to the molecular size of low molecular weight heparins and gastrointestinal inactivation, passage into breast milk and oral absorption by the nursing mothers and receiving nadroparin should be advised not to breastfeed as a precaution.
Fertility
There are no clinical studies on the effect of nadroparin on fertility.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Adverse reactions are listed below by system, organ, class and frequency.
Adverse reactions are classified according to system organ class and according to the frequency convention: very common ≥1 / 10, common ≥1 / 100 to
* In some cases you may notice the appearance of fixed nodules which are not indicative of a heparin encystment. These nodules generally disappear after a few days.
1 Calcinosis is more common in patients with abnormal calcium phosphate production, as well as in some cases of chronic renal failure.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicine is important, as it allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via www.agenziafarmaco.gov. it / it / responsible
04.9 Overdose
Symptoms and signs
The most obvious clinical manifestation of overdose, both subcutaneous and intravenous, is haemorrhage. In this case, a platelet count should be taken and other coagulation parameters measured.
Minor bleeding rarely requires specific therapy and it is usually sufficient to reduce or delay subsequent doses of nadroparin.
Treatment
Only in severe cases should the use of protamine sulfate be considered, which largely neutralizes the anticoagulant effect of nadroparin, although part of the antiXa activity remains.
0.6 ml of protamine sulphate neutralizes about 950 I.U. antiXa of nadroparin. For the quantity of protamine to be injected, the time elapsed since the heparin injection must be taken into account and, if necessary, a reduction in the protamine dose must be made.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotics - heparin derivatives
ATC code: B01AB06
Mechanism of action
Nadroparin is a low molecular weight heparin obtained by depolymerization of standard heparin. It is a glycosaminoglycan with an average molecular weight of about 4300 daltons.
Nadroparin exhibits a high binding affinity with plasma anti-thrombin III (ATIII) protein. This binding leads to an acceleration of the inhibition of factor Xa, which contributes to the high anti-thrombotic potential of nadroparin.
Other mechanisms contributing to the anti-thrombotic activity of nadroparin include stimulation of the tissue factor TFP1 inhibitor, activation of fibrinolysis through direct release of tissue plasminogen activator from endothelial cells, and modification of bleeding parameters (decrease blood viscosity and increased fluidity of platelet and granulocyte membranes).
Pharmacodynamic effects
Nadroparin has a high antiXa / anti-IIa activity ratio. This results in a rapid and prolonged "antithrombotic activity over time.
05.2 Pharmacokinetic properties
The pharmacokinetic properties of nadroparin were determined on the basis of its biological activity, ie by evaluating the anti-factor Xa activity.
Absorption
Peak anti-Xa activity (Cmax) is reached approximately 3-5 hours (tmax) after subcutaneous administration.
Bioavailability is almost complete (approximately 88%).
After i.v. injection, the anti-Xa peak plasma level is reached within less than 10 minutes, and the half-life is approximately 2 hours.
Elimination
The elimination half-life after subcutaneous injection is approximately 3.5 hours.
However, antiXa activity is detectable for at least 18 hours after an injection of 1900 IU antiXa.
Special populations
Senior citizens
Renal function generally decreases with age so that elimination is slower in the elderly (see section 5.2 Pharmacokinetic properties: renal insufficiency below). The possibility of renal insufficiency in this age group and the Dosage should be adjusted accordingly (see section 4.4 Special warnings and precautions for use).
Kidney failure
In a clinical study on the pharmacokinetics of nadroparin administered intravenously in patients with varying degrees of renal insufficiency, a correlation was found between nadroparin clearance and creatinine clearance. Compared with healthy volunteers, the mean AUC and elimination half-life in patients with moderate renal impairment (creatinine clearance 36-43 ml / min) were increased by 52 and 39%, respectively.
In these patients, the mean plasma clearance of nadroparin was decreased by 63% from normal. A large inter-individual variability was observed in the study. In subjects with severe renal impairment (creatinine clearance 10-20 mL / min) both mean AUC and half-life were increased by 95% and 112% respectively in comparison. to healthy volunteers Plasma clearance in patients with severe renal impairment was reduced by 50% of that observed in patients with normal renal function.
Data from previously conducted studies indicate that a slight accumulation of nadroparin may occur in patients with mild to moderate renal impairment (creatinine clearance equal to or greater than 30 ml / min and less than 60 ml / min), in patients receiving nadroparin for treatment of thromboembolic disorders, unstable angina and non-Q myocardial infarction for which dose reduction may be considered (see sections 4.2 Posology and method of administration and 4.4 Special warnings and precautions for use).
In patients with severe renal impairment (creatinine clearance 3 to 6 mL / min) undergoing hemodialysis, both mean AUC and half-life were increased by 62 and 65%, respectively, compared to healthy volunteers. Plasma clearance in hemodialysis patients with severe renal impairment was reduced by 67% compared to that seen in patients with normal renal function (see sections 4.2 Posology and method of administration and 4.4 Special warnings and precautions for use).
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive and developmental toxicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Calcium hydroxide solution or diluted hydrochloric acid, water for injections.
06.2 Incompatibility
Do not mix with other preparations.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
FRAXIPARINA 2.850 I.U. antiXa / 0.3 ml solution for injection: 6 type I colorless glass pre-filled syringes
FRAXIPARINA 3,800 I.U. antiXa / 0.4 ml solution for injection: 6 pre-filled graduated type I colorless glass syringes
FRAXIPARINA 5,700 I.U. antiXa / 0.6 ml solution for injection: 10 pre-filled graduated colorless glass syringes Type I
FRAXIPARINA 7,600 I.U. antiXa / 0.8 ml solution for injection: 10 pre-filled graduated colorless glass syringes Type I
FRAXIPARINA 9.500 I.U. antiXa / 1 ml solution for injection: 10 pre-filled graduated colorless Type I glass syringes
06.6 Instructions for use and handling
Handling: see section 4.2 Posology and method of administration.
The nadroparin solution for injection should be visually inspected prior to use for the presence of particulate matter or color change. If any change is visually noted, the solution should be discarded.
The syringes are for single use only and any unused contents of each syringe should be discarded. Solutions should not be mixed with other preparations or re-administered.
USE OF THE SAFETY DEVICE
After the injection, prepare the safety device of the FRAXIPARINA syringe.
Hold the syringe sleeve with one hand, pull firmly on the syringe ring with the other hand to unlock the sleeve and push until it clicks into place. The needle used is now fully protected.
Do not freeze. Do not refrigerate as cold injections can be painful.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Aspen Pharma Trading Limited 3016 Lake Drive
Citywest Business Campus
Dublin 24
Ireland
08.0 MARKETING AUTHORIZATION NUMBER
6 pre-filled syringes 2,850 I.U. antiXa / 0.3 ml - AIC 026736064
6 pre-filled syringes 3,800 I.U. antiXa / 0.4 ml - AIC 026736076
10 pre-filled syringes 5,700 I.U. antiXa / 0.6 ml - AIC 026736088
10 pre-filled syringes 7,600 I.U. antiXa / 0.8 ml - AIC 026736090
10 pre-filled syringes 9,500 I.U. antiXa / 1 ml - AIC 026736102
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 1 February 1993 / Renewal: February 2008
10.0 DATE OF REVISION OF THE TEXT
June 2017
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