FRAGMIN

Recommended dosage for adults (i) Prevention of clotting during haemodialysis and haemofiltration Administer Fragmin into the arterial side of the dialyzer or intravenously. V. bolus injection of Fragmin 30-40 IU (anti-Factor Xa)/kg bodyweight, followed by an infusion of 10-15 IU (anti-Factor Xa)/kg bodyweight/hour.

(b) Short-term haemodialysis or haemofiltration - duration of haemodialysis/haemofiltration less than 4 hours: A single bolus injection of 5000 IU can be administered, either intravenously or into the arterial side of the extracorporeal system, at the start of the procedure.

V. bolus injection of Fragmin 30-40 IU (anti-Factor Xa)/kg bodyweight, followed by an infusion of 10-15 IU (anti-Factor Xa)/kg bodyweight/hour. ). V. bolus injection of Fragmin 5-10 IU (anti-Factor Xa)/kg bodyweight, followed by an infusion of 4-5 IU (anti-Factor Xa)/kg bodyweight/hour.

4 IU (anti-Factor Xa)/ml. When considered necessary, it is recommended that the antithrombotic effect of Fragmin be monitored by analysing anti-Factor Xa activity using a suitable chromogenic substrate assay. This is because Fragmin has only a moderate prolonging effect on clotting time assays such as APTT or thrombin time.

(ii) Treatment of venous thromboembolism (VTE) Fragmin can be administered subcutaneously either as a single daily injection or as twice daily injections. (a) Once daily administration 200 IU/kg body weight is administered sc. once daily.

Monitoring of the anticoagulant effect is not necessary. The single daily dose should not exceed 18,000 IU. (b) Twice daily administration A dose of 100 IU/kg body weight administered sc. twice daily can be used for patients with increased risk of bleeding.

Monitoring of the treatment is generally not necessary but can be performed with a functional anti-Factor Xa assay. Maximum plasma levels are obtained 3-4 hours after sc. injection, when samples should be taken. 0 IU (anti-Factor Xa)/ml.

Simultaneous anticoagulation with oral vitamin K antagonists can be started immediately. Treatment with Fragmin is continued until the prothrombin complex levels (factor II, VII, IX and X) have decreased to a therapeutic level. At least five days of combined treatment is normally required.

(iii) Unstable coronary artery disease 120 IU/kg body weight are administered subcutaneously twelve hourly for up to 8 days if considered of benefit by the physician. The maximum dose is 10,000 IU/12 hours Patients needing treatment beyond 8 days, while awaiting angiography/revascularisation, should receive a fixed dose of either 5,000 IU (women < 80 kg and men <70 kg) or 7,500 IU (women ≥80 kg and men ≥70 kg) 12 hourly.

Treatment is recommended to be given until the day of the revascularisation procedure (PTCA or CA BG) but not for more than 45 days. Paediatric population Treatment of symptomatic venous thromboembolism (VTE) in paediatric patients 1 month of age and older.

A concentration of 2,500 IU/ml is recommended to ensure accuracy of dosing for the youngest age cohort. 6). For children under 3 years of age, a presentation without benzyl alcohol should be used. Treatment of symptomatic venous thromboembolism in paediatric patients The recommended starting dose according to paediatric age is provided in the table below.

0 ml; if it is below/above this range, a less/more concentrated (respectively) solution for administration should be prepared. 0 ml of the solution as supplied and then add diluent (diluent volume is expressed as a multiple of V); administer the correct volume of the diluted solution.

For children >20 kg, the 12,500 IU/ml concentration may also be administered directly, without dilution. ** The 10,000 IU/ml (10 ml vial) and 25,000 IU/ml (4 ml vial) multidose vials contain benzyl alcohol. For children under 3 years of age, a presentation without benzyl alcohol should be used.

*** For children >50 kg, the 25,000 IU/ml solution may also be administered directly, without dilution. 6). Monitoring Anti-Xa levels in children After initiation of Fragmin, anti-Xa level should initially be measured after the first, second or third dose.

Samples for anti-Xa level should be drawn 4 hours after administration. Doses should be adjusted in increments of 25 IU/kg to […]

About 3% of the patients having had prophylactic treatment reported side-effects. The reported adverse reactions, which may possibly be associated to dalteparin sodium, are listed in the following table by system organ class and frequency group: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000).

System Organ Class Frequency Adverse reactions Common Mild thrombocytopenia (type I), which usually is reversible during the treatment Blood and lymphatic system disorders Not Known* Immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications) Uncommon Hypersensitivity Immune system disorders Not Known* Anaphylactic reactions Metabolism and nutrition disorders Common Hyperkalaemia Nervous system disorders Not Known* Intracranial bleeds have been reported and some have been fatal Cardiac disorders Not Known* Prosthetic cardiac valve thrombosis Vascular disorders Common Haemorrhage Gastrointestinal disorders Not Known* Retroperitoneal bleeds have been reported and some have been fatal Hepatic and biliary disorders Common Transient elevation of transaminases Uncommon Urticaria, pruritus Rare Skin necrosis, transient alopecia Skin and subcutaneous tissue disorders Not Known* Rash Musculoskeletal and connective tissue disorders Uncommon Osteoporosis (in connection with long-term treatment) General disorders and administration site conditions Common Subcutaneous haematoma at the injection site Pain at the injection site Injury, Poisoning and Procedural Complications Not Known* Spinal or epidural hematoma *(cannot be established from available data) The risk of bleeding is depending on dose.

Most bleedings are mild. Severe bleedings have been reported, some cases with fatal outcome. Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. 4). Long term treatment with heparin has been associated with a risk of osteoporosis.

Although this has not been observed with dalteparin, the risk of osteoporosis cannot be excluded. Paediatric population Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. The safety of long term dalteparin administration has not been established.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Do not administer by the intramuscular route. Due to the risk of haematoma, intramuscular injection of other medical preparations should be avoided when the twenty-four hour dose of dalteparin exceeds 5,000 IU. g. 5). Caution shall also be observed at high-dose treatment with dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).

The concomitant use with drugs affecting hemostasis, such as thrombolytic agents, other anticoagulants, NSAIDs, platelet inhibitors, or dextran may enhance the anticoagulant effect of dalteparin and is not recommended. 5). It is recommended that platelets be counted before starting treatment with Fragmin and monitored regularly.

Special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100,000/μl) associated with positive or unknown results of in-vitro tests for anti-platelet antibody in the presence of Fragmin or other low molecular weight (mass) heparins and/or heparin.

Fragmin induces only a moderate prolongation of the APTT and thrombin time. Accordingly, dosage increments based upon prolongation of the APTT may cause overdosage and bleeding. Therefore, prolongation of the APTT should only be used as a test of overdosage.

Monitoring Anti-Xa Levels Monitoring of Anti-Xa Levels in patients using Fragmin is not usually required but should be considered for specific patient populations such as paediatrics, those with renal failure, those who are very thin or morbidly obese, pregnant or at increased risk for bleeding or rethrombosis Where monitoring is necessary, laboratory assays using a chromogenic substrate are considered the method of choice for measuring anti-Xa levels.

Activated partial thromboplastin time (APTT) or thrombin time should not be used because these tests are relatively insensitive to the activity of dalteparin. 9). Patients under chronic haemodialysis with dalteparin need as a rule fewer dosage adjustments and as a result fewer controls of anti-Xa levels.

2). Patients with severely disturbed hepatic function may need a reduction in dosage and should be monitored accordingly. If a transmural myocardial infarction occurs in patients where thrombolytic treatment might be appropriate, this does not necessitate discontinuation of treatment with Fragmin, but might increase the risk of bleeding.

As individual low molecular weight (mass) heparins have differing characteristics, switching to an alternative low molecular weight heparin should be avoided. The directions for use relating to each specific product must be observed as different dosages may be required.

Interchangeability with other anticoagulants Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin, Other low molecular weight heparins, or synthetic polysaccharides. Each of these medicines differ in their starting raw materials, manufacturing process, physico- chemical, biological, and clinical properties, leading to differences in biochemical identity, dosing, and possibly clinical efficacy and safety.

Each of these medicines is unique and has its own instructions for use. Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre- existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs.

The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

When neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal puncture is employed, patients are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants.

The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be monitored frequently for signs and symptoms of neurological impairment when anticoagulation is given in connection with epidural/spinal anaesthesia.

Insertion or removal of the epidural or spinal catheter should be postponed to 10-12 hours after dalteparin doses administered for thrombosis prophylaxis, while in those receiving higher therapeutic dalteparin doses (such as 100 IU/kg -120 IU/kg every 12 hours or 200 IU/kg once daily), the interval should be a minimum of 24 hours.

Should a physician, as a clinical judgement, decide to administer anticoagulation in the context of epidural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction.

Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform immediately a nurse or a clinician […]

g. history of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (type II); acute gastroduodenal ulcer; cerebral haemorrhage; known haemorrhagic diathesis or other active haemorrhage; serious coagulation disorders; acute or sub-acute septic endocarditis; injuries to and operations on the central nervous system, eyes and ears.

In patients receiving Fragmin for treatment rather than prophylaxis, local and/or regional anaesthesia in elective surgical procedures is contra-indicated with high doses of dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).