Fraxiparine

Fraxiparine

nadroparin calcium

Manufacturer:

Aspen Asia

Distributor:

Cordial Trading
/
Primal
Full Prescribing Info
Contents
Nadroparin calcium.
Description
FRAXIPARINE [Nadroparin calcium solution for injection (9,500 anti-Xa IU/ml)]: Pre-filled syringes: 0.3 ml of solution is equivalent to 2,850 anti-Xa IU.
0.4 ml of solution is equivalent to 3,800 anti-Xa IU.
Excipients/Inactive Ingredients: Calcium hydroxide solution or dilute hydrochloric acid for pH adjustment (5 to 7.5), Water for Injections.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Nadroparin is a low molecular weight heparin made by depolymerisation of standard heparin. It is a glycosaminoglycan with a mean molecular weight of approximately 4,300 daltons.
Nadroparin exhibits a high-affinity binding to the plasma protein anti-thrombin III (ATIII). This binding leads to an accelerated inhibition of factor Xa, which contributes to the high anti-thrombotic potential of nadroparin.
Other mechanisms that contribute to the anti-thrombotic activity of nadroparin include stimulation of tissue factor pathway inhibitor (TFP1), activation of fibrinolysis via direct release of tissue plasminogen activator from endothelial cells, and the modification of haemorrheological parameters (decreased blood viscosity and increased platelet and granulocyte membrane fluidity).
Pharmacodynamic Effects: Nadroparin has a high ratio of anti-Xa to anti-IIa activity. It has both immediate and prolonged anti-thrombotic action.
Compared with unfractionated heparin, nadroparin has less effect on thrombocyte function and aggregation and only a slight effect on primary haemostasis.
Pharmacokinetics: The pharmacokinetic properties of nadroparin have been assessed on the basis of biological activity, i.e. measurement of anti-factor Xa activity.
Absorption: Following subcutaneous administration, the peak anti-Xa activity (Cmax) is reached after approximately 3 to 5 hours (Tmax).
Bioavailability is almost complete (around 88 %).
After i.v. injection, the peak plasma anti-Xa level is reached within less than 10 minutes, and the half-life is around 2 hours.
Elimination: The elimination half-life after subcutaneous injection is approximately 3.5 hours. However, anti-Xa activity is detectable for at least 18 hours following an injection of 1900 anti-Xa IU.
Special Patient Populations: Elderly: Renal function generally decreases with age so elimination is slower in the elderly (see Renal Impairment as follows). The possibility of renal impairment in this age group must be considered and the dosage adjusted accordingly (see Precautions).
Renal Impairment: In a clinical study investigating the pharmacokinetics of nadroparin administered intravenously in patients with varying degrees of renal impairment, a correlation was found between nadroparin clearance and the creatinine clearance. In patients with moderate renal impairment (creatinine clearance 36-43 ml/min), both mean AUC and half-life were increased by 52 and 39% respectively compared with healthy volunteers. In these patients, mean plasma clearance was decreased to 63% of normal. Wide 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 compared with healthy volunteers. Plasma clearance in patients with severe renal impairment was decreased to 50% of that observed in patients with normal renal function. In subjects with severe renal impairment (creatinine clearance 3-6 ml/min) on haemodialysis, both mean AUC and half-life were increased by 62 and 65% respectively compared with healthy volunteers. Plasma clearance in haemodialysis patients with severe renal impairment was decreased to 67% of that observed in patients with normal renal function (see Precautions).
Indications/Uses
Prophylaxis treatment of venous thromboembolic disease of moderate or high risk during surgery.
Treatment of constituted deep vein thrombosis.
Treatment of unstable angina and non-Q wave myocardial infarction during acute phase, in combination with aspirin.
Prevention of coagulation in the extracorporeal circuit during haemodialysis.
Dosage/Direction for Use
Particular attention should be paid to the specific dosing instructions for each proprietary Low Molecular Weight Heparin, as different unit systems (units or mg) are used to express doses. Nadroparin should therefore not be used interchangeably with other low molecular weight heparins during ongoing treatment. In addition, care should be taken to use the correct formulation of nadroparin, either single or double strength, as this will affect the dosing regimen.
Nadroparin is not intended for IM administration.
Platelet count must be monitored throughout nadroparin treatment (see Precautions).
Specific recommendations regarding the timing of nadroparin dosing surrounding spinal/epidural anaesthesia or spinal lumbar puncture should be followed (see Precautions).
In the prophylaxis or curative treatment, FRAXIPARINE should be administered by the subcutaneous route. In the prevention of clotting during haemodialysis, FRAXIPARINE should be administered into the arterial line at the start of each session.
Subcutaneous injection technique: The usual site for subcutaneous injection is on the right or left side of the abdominal wall, but the thigh may be used as an alternative. To avoid loss of the solution when using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection. The needle should be inserted perpendicularly into a pinched-up fold of skin which should be held gently but firmly until injection has been completed. The injection site should not be rubbed.
Prophylaxis of thromboembolic disorders: General surgery: FRAXIPARINE should be administered as a single daily dose of 0.3 ml for a usual duration of 7 days at least; in all cases prophylaxis should be continued throughout the risk period and at least until the patient is ambulatory. In general surgery the first dose should be given 2 to 4 hours pre-operatively.
Orthopaedic surgery: Initial doses should be given 12 hours before surgery and 12 hours after the end of surgery. These and subsequent once daily doses should be adjusted to body weight based on the table as follows. Treatment should continue for at least 10 days; in all cases, prophylaxis should be continued throughout the risk period and at least until the patient is ambulatory. (See Table 1.)

Click on icon to see table/diagram/image

Treatment of thromboembolic disorders: Oral anticoagulant therapy is initiated as soon as possible unless there is a contraindication. Treatment with FRAXIPARINE should not be stopped before International Normalised Ratio (INR) target is reached.
FRAXIPARINE should be given subcutaneously twice daily (every 12 hours) for a usual duration of 10 days with the dose adjusted to body weight shown as follows: See Table 2.

Click on icon to see table/diagram/image

Treatment of unstable angina and non-Q wave myocardial infarction: Nadroparin should be administered in 2 daily subcutaneous injection (every 12 hours) of 86 IU anti-Xa/kg each, in combination with aspirin of which the recommended dose is 75-325mg orally, after a loading dose of 160-325mg.
The initial dose of FRAXIPARINE should be given as an IV bolus followed by a SC injection of 86 IU anti-Xa/kg. The usual treatment duration is around 6 days up to clinical stabilisation, with a dose adjusted to body weight shown as follows: See Table 3.

Click on icon to see table/diagram/image

If a thrombolytic treatment is necessary, as there are no clinical data available concerning the concomitant administration of nadroparin and thrombolytic drug, it is recommended to withdraw the treatment with FRAXIPARINE and to follow the patient as usual.
Prevention of clotting during haemodialysis: Optimisation of dosage is required for each individual patient and taking into account the technical conditions of the dialysis. FRAXIPARINE is usually given as a single dose into the arterial line at the start of each session. For patients without increased risk of haemorrhage the following initial doses are suggested according to body weight: See Table 4.

Click on icon to see table/diagram/image

In patients at risk of haemorrhage, dialysis sessions could be done using halved doses.
An additional smaller dose may be given during dialysis for sessions lasting longer than 4 hours. The dose in subsequent dialysis sessions should be adjusted as necessary according to initially observed effect.
Patients should be carefully monitored throughout each dialysis session for signs of bleeding or clotting in the dialysis circuit.
Children and Adolescents: Nadroparin is not recommended in children and adolescents as there are insufficient safety and efficacy data to establish dosage in patients aged less than 18 years.
Overdosage
Symptoms and Signs: Haemorrhage is the major clinical sign of subcutaneous or intravenous overdosage. The platelet count and other coagulation parameters should be measured. Minor bleeding rarely requires specific therapy, and reducing or delaying subsequent doses of nadroparin is usually sufficient.
Treatment: The use of protamine sulphate should be considered only in more serious cases. It largely neutralises the anti-coagulant effect of nadroparin but some anti-Xa activity will remain. 0.6 ml of protamine sulphate neutralises about 950 IU anti-Xa nadroparin. The amount of protamine to be injected should take into account time elapsed from the injection of heparin, and a dose reduction of protamine may be appropriate.
Contraindications
Nadroparin is contraindicated in cases of: hypersensitivity to nadroparin or any of the excipients of nadroparin injections; history of thrombocytopenia with nadroparin (see Precautions); active bleeding or increased risk of haemorrhage, in relation with haemostasis disorders, except for disseminated intravascular coagulation not induced by heparin; organic lesion likely to bleed (such as active peptic ulceration); haemorrhagic cerebrovascular accident; acute infectious endocarditis; severe renal impairment (creatinine clearance less than 30 ml/min) in patients receiving treatment for thromboembolic disorders, unstable angina, and non-Q wave myocardial infarction.
Special Precautions
Heparin-induced Thrombocytopenia: Because of the possibility of heparin-induced thrombocytopenia, platelet count should be monitored throughout the course of treatment with nadroparin.
Rare cases of thrombocytopenia, occasionally severe, have been reported, which may be associated with arterial or venous thrombosis. Such diagnosis should be considered in the following situations: thrombocytopenia; any significant decrease in platelet level (30 to 50% compared with the baseline value); worsening of the initial thrombosis while on therapy; thrombosis occuring on treatment; disseminated intra-vascular coagulation.
In this event, nadroparin treatment must be discontinued.
These effects are probably of immuno-allergic nature and in the case of a first treatment are reported mainly between the 5th and the 21st day of therapy, but may occur much earlier if there is a history of heparin-induced thrombocytopenia.
If there is a history of thrombocytopenia occurring with heparin (either standard or low molecular weight heparin), treatment with nadroparin may be considered if necessary. In such cases, careful clinical monitoring and assessment of platelet count should be performed at least daily. If thrombocytopenia occurs, treatment should be discontinued immediately.
When thrombocytopenia occurs with heparin (either standard or low molecular weight heparin), substitution with a different anti-thrombotic class should be considered. If not available, then substitution with another low molecular weight heparin may be considered if the administration of heparin is necessary. In such cases, platelet count monitoring should be performed at least daily and the treatment should be discontinued as soon as possible, since cases of initial thrombocytopenia continuing after substitution have been described (see Contraindications).
In vitro platelet aggregation tests are only of limited value in the diagnosis of heparin induced thrombocytopenia.
Caution should be exercised when nadroparin is administered in the following situations as they may be associated with an increased risk of bleeding: hepatic failure; severe arterial hypertension; history of peptic ulceration or other organic lesion likely to bleed; vascular disorder of the chorio-retina; during the post-operative period following surgery of the brain, spinal cord or eye.
Renal Impairment: Nadroparin is known to be mainly excreted by the kidney, which results in increased nadroparin exposure in patients with renal impairment (see Pharmacology: Pharmacokinetics: Special Patient Populations: Renal Impairment under Actions). Patients with impaired renal function are at increased risk of bleeding and should be treated with caution.
The decision on whether a dose reduction is appropriate for patients with creatinine clearance 30 to 50ml/min should be based on the physician's assessment of an individual patient's risk of bleeding versus the risk of thromboembolism.
Hyperkalaemia: Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients with raised plasma potassium, or at risk of increased plasma potassium levels, such as patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis or taking drugs that may cause hyperkalaemia (e.g. angio-tensin-converting enzyme (ACE) inhibitors, Nonsteroidal anti-inflammatory drugs (NSAIDs)).
The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible.
Plasma potassium should be monitored in patients at risk.
Spinal/epidural anaesthesia/spinal lumbar puncture and concomitant drugs: Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anaesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters; Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; A history of traumatic or repeated epidural or spinal punctures; A history of spinal deformity or spinal surgery.
Therefore, the concomitant prescription of a neuraxial blockade and of an anticoagulant therapy should be decided after careful individual benefit / risk assessment in the following situations: in patients already treated with anti-coagulants or to be anticoagulated, the benefits of a neuraxial blockade must be carefully balanced against the risks; in patients planned to undergo elective surgery with neuraxial blockade, the benefits of anti-coagulant therapy must be carefully balanced against the risks.
To reduce the potential risk of bleeding associated with the concurrent use of nadroparin and epidural or spinal anaesthesia/analgesia, the placement and removal of the catheter is best performed when the anticoagulant effect of nadroparin is low, considering the dose of anticoagulant and its elimination half-life. In the case of patients with spinal lumbar puncture, spinal anaesthesia or epidural anaesthesia, a minimum of 12 hours should elapse between the nadroparin injection at prophylactic doses or 24 hours at treatment doses and the insertion or the removal of the spinal/epidural catheter or needle. For patients with renal impairment longer intervals may be considered.
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Salicylates, non-steroidal anti-inflammatory and anti-platelet drugs: In the prophylaxis or treatment of venous thromboembolic disorders and in the prevention of clotting during haemodialysis, the concomitant use of aspirin, other salicylates, NSAIDs, and anti-platelet agents is not recommended, as they may increase the risk of bleeding. Where such combinations cannot be avoided, careful clinical and biological monitoring should be undertaken.
In clinical studies for the treatment of unstable angina and non-Q wave myocardial infarction, nadroparin was administered in combination with up to 325 mg aspirin per day (see Dosage & Administration).
Cutaneous Necrosis: Cutaneous necrosis has been reported very rarely. It is preceded by purpura or infiltrated or painful erythematous blotches, with or without general signs. In such cases, treatment should be immediately discontinued.
Latex Allergy: The needle shield of the pre-filled syringe may contain dry natural latex rubber that has the potential to cause allergic reactions in latex sensitive individuals.
Use in Elderly: It is recommended that renal function is assessed before initiating treatment (see Contraindications).
Use In Pregnancy & Lactation
Fertility: There are no clinical studies on the effect of nadroparin on fertility.
Pregnancy: Studies in animals have not shown any teratogenic or foetotoxic effects. However, there is only limited clinical data concerning transplacental passage of nadroparin in pregnant women. Therefore, the use of nadroparin during pregnancy is not advised, unless the therapeutic benefits outweigh the possible risks.
Lactation: There is limited information on the excretion of nadroparin in breast milk. Therefore, use of nadroparin during breast feeding is not advised.
Adverse Reactions
Adverse reactions are listed as follows by system organ class and frequency.
The following convention has been used for the classification of adverse reactions in terms of frequency: Very common ≥1/10, common ≥1/100 to <1/10, uncommon ≥1/1000 to <1/100, rare ≥1/10,000 to <1/1000, very rare <1/10,000.
Blood and lymphatic system disorders: Very common: Haemorrhagic manifestations at various sites, more frequent in patients with other risk factors (see Contraindications and Interactions).
Rare: Thrombocytopenia, (including heparin-induced thrombocytopenia) (see Precautions), thrombocytosis.
Very rare: Eosinophilia, reversible following treatment discontinuation.
Immune system disorders: Very rare: Hypersensitivity reactions (including angioedema and cutaneous reactions), anaphylactoid reaction.
Metabolism and nutrition disorders: Very rare: Reversible hyperkalaemia related to heparin-induced aldosterone suppression, particularly in patients at risk (see Precautions).
Hepato-biliary disorders: Common: Raised transaminases, usually transient.
Reproductive system and breast disorders: Very rare: Priapism.
Skin and subcutaneous tissue disorders: Rare: Rash, urticaria, erythema, pruritus.
Very rare: Cutaneous necrosis, usually occurring at the injection site (see Precautions).
General disorders and administration site conditions: Very common: Small haematoma at the injection site.
In some cases, the emergence of firm nodules, which do not indicate an encystment of the heparin may be noted. These nodules usually disappear after a few days.
Common: Injection site reaction.
Rare: Calcinosis at the injection site.
Calcinosis is more frequent in patients with abnormal calcium phosphate product, such as in some cases of chronic renal failure.
Drug Interactions
Nadroparin should be administered with caution in patients receiving oral anti-coagulant agents, systemic (gluco-) corticosteroids and dextrans. When oral anti-coagulant therapy is initiated in patients receiving nadroparin, treatment with nadroparin should be continued until the International Normalisation Ratio (INR) is stabilised at the target value.
Caution For Usage
Instructions for Use/Handling: FRAXIPARINE should be visually inspected for any particulate matter and discoloration before use. If any visual change is noted, the solution must be discarded.
Syringes are intended for single use only, and any unused portion of each syringe must be discarded. Solutions must not be mixed with other preparations or re-dispensed.
After administration the needle shield must be slid over the exposed needle, so that the needle is completely covered. The syringe can then be disposed of appropriately.
The plastic "flip off" cap must be removed from multi-dose vials, and only the middle of the aluminium cap removed, so that the small circle on the rubber stopper is visible. The rubber stopper must be disinfected before inserting the needle.
Incompatibilities: Do not mix with other products.
Storage
Do not freeze. Do not refrigerate as cold injections may be painful.
Patient Counseling Information
Instructions for self administration using a pre-filled syringe: Always use FRAXIPARINE exactly as your doctor or nurse has instructed you. You should ask their advice if you are having any difficulties injecting FRAXIPARINE.
1. Wash your hands thoroughly with soap and water and dry them with a towel.
2. Sit or lie down in a comfortable position.
The injection is given in the side of the lower stomach area. Alternate the left and right side of the stomach at each injection.
3. Clean the injection area with an alcohol swab.
4. Pull off the cap that protects the needle. Discard the cap.
If the volume in the syringe is more than you need, you must remove the excess before you inject yourself: Hold the syringe with the needle pointing straight down.
Push the syringe plunger gently down until the bottom of the bubble sits on the line marked with the volume your doctor has prescribed for you.
Drip the fluid that comes out of the needle on to a tissue, and discard.
The syringe is now ready to use.
Important note: Do not touch the needle or allow it to come in contact with any surface before the injection.
The presence of a small air bubble in the syringe is normal. Do not try to remove this air bubble before making the injection.
5. Gently pinch the skin that has been cleaned to make a fold. Hold the fold between the thumb and the forefinger during the entire injection.
6. Hold the syringe firmly by the finger hold. Insert the full length of the needle straight (at an angle of 90°) into the skin fold.
7. Inject ALL of the contents of the syringe by pressing down on the plunger as far as it goes.
8. Remove the syringe from the skin. The injection site should not be rubbed.
9. After injection use the safety shield to protect from needle injuries. To do this, hold the syringe in one hand by gripping the safety shield, then use the other hand to pull firmly on the finger hold. This unlocks the shield. Slide the shield up the body of the syringe until it locks into position over the needle.
10. Dispose of the used syringe as your nurse or doctor has instructed you.
ATC Classification
B01AB06 - nadroparin ; Belongs to the class of heparin group. Used in the treatment of thrombosis.
Presentation/Packing
Inj (pre-filled syringe) 2,850 AXa IU/0.3 mL x 10's. 3,800 AXa IU/0.4 mL x 10's.
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