4.1. Therapeutic indications

Prevention of clotting in the extracorporeal circulation during haemodialysis or haemofiltration, in patients with chronic renal insufficiency or acute renal failure.

Paediatric population

Treatment of symptomatic venous thromboembolism (VTE) in paediatric patients 1 month of age and older.

4.2. Posology and method of administration

Recommended dosage for adults

(i) Prevention of clotting during haemodialysis and haemofiltration

Administer Fragmin into the arterial side of the dialyzer or intravenously.

In chronic renal insufficiency for patients with no known additional bleeding risk, the dosage is:

(a) Long-term haemodialysis or haemofiltration - duration of haemodialysis/haemofiltration more than 4 hours;

An iv 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. Alternatively, an iv 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.

The 5000 IU starting dose for the single bolus dosing regimen can be adjusted, session-to-session, based on the outcome of the previous dialysis; the dose may be increased or decreased in steps of 500 or 1000 anti-Xa IU (according to clinical judgement) until a satisfactory outcome is obtained (see section 5.1.).

In acute renal failure, or chronic renal failure in patients with a high risk of bleeding, the dosage is:

An iv 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.

The plasma anti-Factor Xa levels should be within the range 0.2-0.4 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.

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. When dilution is required, it should be performed by a healthcare professional (see section 6.6). 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.

Table 1 - Starting doses for paediatric patients with symptomatic VTE

Age group

Starting dose

1 month to less than 2 years

150 IU/kg twice daily

2 years to less than 8 years

125 IU/kg twice daily

8 years to less than 18 years

100 IU/kg twice daily

Table 2 - Paediatric dilution table

Age

Recommended Concentration for Administration

Concentration as supplied*

10,000 IU/ml**

25,000 IU/ml**

1 month - 2 years

2,500 IU/ml

V (active) + 3V (diluent)

V (active) + 9V (diluent)

2 years - 8 years

10,000 IU/ml

No dilution required

V (active) + 1.5V (diluent)

8 years - 17 years

10,000 IU/ml

No dilution required

V (active) + 1.5V (diluent)***

The final volume for injection should be between 0.15 ml and 1.0 ml; if it is below/above this range, a less/more concentrated (respectively) solution for administration should be prepared.

* Withdraw a convenient volume (V) of at least 1.0 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.

Fragmin is compatible with sodium chloride (9 mg/ml) or glucose (50 mg/ml) infusion solutions in glass bottles and plastic containers (see section 6.6).

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 achieve target anti-Xa level between 0.5 IU/ml and 1 IU/ml and anti-Xa level measured after each adjustment. The maintenance dose should be individualised based on the dose that achieves target anti-Xa level collected 4 hours after administration.

Monitoring of anti Xa levels should be continued until an adequate maintenance dose is established and continued periodically to maintain target anti-Xa level. In the youngest children, initial monitoring of anti-Xa level is recommended to start after the first dose and more frequent monitoring may be required afterwards to guide dose adjustments until the target anti-Xa levels are achieved (see sections 5.1 and 5.2).

In the case of low and changing physiologic renal function such as in neonates, close monitoring of anti-Xa levels is warranted.

As with all antithrombotic agents, there is a risk of systemic bleeding with Fragmin administration. Care should be taken with Fragmin use in high dose treatment of newly operated patients. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of hemoglobin, and anti-Xa determinations.

The safety and efficacy of dalteparin sodium for prophylaxis of VTE in children has not been established. Currently available data on prophylaxis of VTE are described in section 5.1 but no recommendation on a posology can be made.

Elderly

Fragmin has been used safely in elderly patients without the need for dosage adjustment.

Method of administration

Fragmin is administered during haemodialysis and haemofiltration either intravenously or into the arterial side of the dialyzer.

Paediatric population

Fragmin is administered by subcutaneous administration, preferably into the abdominal subcutaneous tissue anterolaterally or posterolaterally, or into the lateral part of the thigh at an angle between 45° and 90°.

Comprehensive instructions for the administration of Fragmin are given in section 3 of the package leaflet.

4.3. Contraindications

Known hypersensitivity to Fragmin or other low molecular weight heparins and/or heparins e.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).

4.4. Special warnings and precautions for use

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.

Caution should be exercised in patients in whom there is an increased risk of bleeding complications, e.g. following surgery or trauma, haemorrhagic stroke, severe liver or renal failure, thrombocytopenia or defective platelet function, uncontrolled hypertension, hypertensive or diabetic retinopathy, patients receiving concurrent anticoagulant/antiplatelet agents (see section 4.5). 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. Appropriate caution ‎should be exercised under specific circumstances of switching anticoagulant therapy (see section ‎4.5).

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. Increasing the dose of dalteparin in an attempt to prolong APTT may result in bleeding (see section 4.9).

Patients under chronic haemodialysis with dalteparin need as a rule fewer dosage adjustments and as a result fewer controls of anti-Xa levels. Patients undergoing acute haemodialysis may be more unstable and should have a more comprehensive monitoring of anti-Xa levels (see section 5.2).

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 if they experience any of these.

If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment may include spinal cord decompression.

There have been no adequate studies to assess the safe and effective use of Fragmin in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of Fragmin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. The use of Fragmin cannot be recommended for this purpose.

At long-term treatment of unstable coronary artery disease, such as e.g., before revascularisation, dose reduction should be considered at reduced kidney function (S-creatinine > 150 μmol/l).

Paediatric population

Anti-Xa levels should be monitored during initiation of therapy and following any dose adjustment (see section 4.2).

There are no data in children with cerebral vein and sinus thrombosis who have a CNS infection. The risk of bleeding should be carefully evaluated before and during therapy with dalteparin.

Use in elderly

Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised.

Excipients

Sodium

Fragmin 10,000 IU (anti-Xa)/4 ml contains 24.2 mg sodium per vial, equivalent to 1.21% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product may be further diluted with sodium-containing solutions (see section 4.2 and section 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

4.5. Interaction with other medicinal products and other forms of interaction

Drugs Increasing Effects of Dalteparin

The possibility of the following interactions with Fragmin should be considered:

(i) An enhancement of the anticoagulant effect by other anticoagulant/antiplatelet agents e.g. aspirin/ dipyridamole, GP IIb/IIIa receptor antagonists, vitamin K antagonists, NSAIDs e.g. indomethacin, cytostatics, dextran, thrombolytics, sulphinpyrazone, probenecid, and ethacrynic acid (see section 4.2 and section 4.4).

(ii) A reduction of the anticoagulant effect may occur with concomitant administration of antihistamines, cardiac glycosides, tetracycline and ascorbic acid.

Because NSAIDs and ASA analgesic/anti-inflammatory doses reduce production of vasodilatory prostaglandins, and thereby renal blood flow and the renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose ASA in patients with renal failure.

However, if there are no specific contraindications, patients with unstable coronary artery disease (unstable angina and non-Q-wave infarction) can be treated with low doses of acetylsalicylic acid.

Drugs Antagonizing Effects of Dalteparin

The concomitant use of dalteparin with andexanet alfa may reduce the effectiveness of dalteparin. Andexanet alfa, a recombinant modified human coagulation factor Xa used for reversal of anticoagulation with apixaban or rivaroxaban, has been shown to bind to heparin-bound anti-thrombin III (ATIII) and may reduce the anticoagulant effect of dalteparin.

Other Interactions

As heparin has been shown to interact with intravenous nitroglycerine, high dose penicillin, quinine and tobacco smoking interaction cannot be ruled out for dalteparin.

Paediatric population

Interaction studies have only been studied in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Dalteparin does not pass the placenta. A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. Fragmin can be used during pregnancy if clinically needed.

If dalteparin is used during pregnancy, the possibility of foetal harm appears remote. However, because the possibility of harm cannot be completely ruled out, dalteparin should be used during pregnancy only if clearly needed.

There are more than 2,000 published cases (studies, case series and case reports) on administration of dalteparin in pregnancy. As compared with unfractionated heparin, a lower bleeding tendency and reduced risk of osteoporotic fracture was reported. The largest prospective study “Efficacy of Thromboprophylaxis as an Intervention during Gravidity” (EThIG), involved 810 pregnant women and investigated a pregnancy-specific scheme for risk stratification (low, high, very high risk of venous thromboembolism) with daily doses of dalteparin between 50 – 150 IU/kg body weight (in single cases up to max. 200 IU/kg body weight). However, only limited randomised controlled studies are available on the use of low molecular weight heparins in pregnancy.

Animal experiments did not show any teratogenic or fetotoxic properties of dalteparin (see section 5.3).

Epidural anaesthesia during childbirth is absolutely contraindicated in women who are being treated with high-dose anticoagulants (see section 4.3). Caution is recommended when treating patients with an increased risk of haemorrhage, such as perinatal women (see section 4.4). In pregnant women during the last trimester, dalteparin anti-Xa half-lives of 4 to 5 hours were measured.

Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses of low molecular weight heparin. In the absence of clear dosing, efficacy and safety information in this circumstance, Fragmin is not recommended for use in pregnant women with prosthetic heart valves.

Breast-feeding

Limited data are available for excretion of dalteparin in human milk. One study in 15 women(between day 3 and 5 of lactation and 2 to 3 hours after receiving prophylactic doses of dalteparin) detected small amounts of anti- factor Xa levels of 2 to 8% of plasma levels in breast milk, equivalent to a milk/plasma ratio of <0.025-0.224. An anticoagulant effect on the infant appears unlikely.

A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Fragmin should be made taking into account the benefit of breast-feeding to the child and the benefit of Fragmin therapy to the woman.

Fertility

Based on current clinical data there is no evidence that dalteparin sodium affects fertility. No effects on fertility, copulation or peri- and postnatal development were noted when dalteparin sodium was tested in animals.

4.7. Effects on ability to drive and use machines

Fragmin does not affect the ability to drive or operate machinery.

4.8. Undesirable effects

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

Blood and lymphatic system disorders

Common

Mild thrombocytopenia (type I), which usually is reversible during the treatment

Not Known*

Immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications)

Immune system disorders

Uncommon

Hypersensitivity

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

Skin and subcutaneous tissue disorders

Uncommon

Urticaria, pruritus

Rare

Skin necrosis, transient alopecia

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. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see section 4.4).

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The anticoagulant effect (i.e. prolongation of the APTT) induced by Fragmin is inhibited by protamine. Since protamine itself has an inhibiting effect on primary haemostasis it should be used only in an emergency.

The prolongation of the clotting time induced by Fragmin may be fully neutralised by protamine, but the anti-Factor Xa activity is only neutralised to about 25-50%. 1 mg of protamine inhibits the effect of 100 IU (anti-Factor Xa) of Fragmin.