1. Name Of The Medicinal Product
Fragmin® 2500IU/5000 IU
2. Qualitative And Quantitative Composition
Active ingredient
Dalteparin sodium (INN)
Quality according to Ph.Eur. and in-house specification.
Potency is described in International anti-Factor Xa units (IU) of the 1st International Standard for Low Molecular Weight Heparin.
Content of active ingredient
Fragmin 2500 IU: single dose syringe containing dalteparin sodium 2,500 IU (anti-Factor Xa) in 0.2 ml solution.
Fragmin 5000 IU: single dose syringe containing dalteparin sodium 5000 IU (anti-Factor Xa) in 0.2 ml solution.
Fragmin syringes do not contain preservatives.
3. Pharmaceutical Form
Solution for injection for subcutaneous administration.
4. Clinical Particulars
4.1 Therapeutic Indications
Peri- and post-operative surgical thromboprophylaxis.
For the 5000 IU Presentation Only:
The prophylaxis of proximal deep venous thrombosis in patients bedridden due to a medical condition, including, but not limited to; congestive cardiac failure (NYHA class III or IV), acute respiratory failure or acute infection, who also have a predisposing risk factor for venous thromboembolism such as age over 75 years, obesity, cancer or previous history of VTE.
4.2 Posology And Method Of Administration
Adults
a) Surgical thromboprophylaxis in patients at moderate risk of thrombosis
2,500IU is administered subcutaneously 1-2 hours before the surgical procedure and thereafter 2,500 IU subcutaneously each morning until the patient is mobilised, in general 5-7 days or longer.
b) Surgical thromboprophylaxis in patients at high risk of thrombosis
2,500 IU is administered subcutaneously 1-2 hours before the surgical procedure and 2,500 IU subcutaneously 8-12 hours later. On the following days, 5,000 IU subcutaneously each morning.
As an alternative, 5,000 IU is administered subcutaneously the evening before the surgical procedure and 5,000 IU subcutaneously the following evenings.
Treatment is continued until the patient is mobilised, in general 5-7 days or longer.
c) Prolonged thromboprophylaxis in hip replacement surgery
5,000IU is given subcutaneously the evening before the operation and 5,000IU subcutaneously the following evenings. Treatment is continued for five post-operative weeks.
If pre-operative administration of Fragmin is not considered appropriate because the patient is at high risk of haemorrhage during the procedure, post-operative Fragmin may be administered (see Section 5.1).
d) Prophylaxis of venous thromboembolism in medical patients: The recommended dose of dalteparin sodium is 5,000 IU once daily. Treatment with dalteparin sodium is prescribed for up to 14 days.
Children
Not recommended for children.
Elderly
Fragmin has been used safely in elderly patients without the need for dosage adjustment.
Method of Administration
By subcutaneous injection, preferably into the abdominal subcutaneous tissue anterolaterally or posterolaterally, or into the lateral part of the thigh. Patients should be supine and the total length of the needle should be introduced vertically, not at an angle, into the thick part of a skin fold, produced by squeezing the skin between the thumb and forefinger; the skin fold should be held throughout the injection.
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; serious coagulation disorders; 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
For the 5000 IU Presentation Only:
Dalteparin should not be used in patients who have suffered a recent (within 3 months) stroke unless due to systemic emboli.
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 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 Interactions Section). Caution shall also be observed at high-dose treatment with dalteparin (such as those needed to treat acute deep
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 Overdosage).
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 Pharmacokinetic properties).
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.
In patients undergoing spinal or epidural anaesthesia, the prophylactic use of heparin maybe very rarely associated with spinal haematomas resulting in prolonged or permanent paralysis. The risk is increased by use of an epidural or spinal catheter for anaesthesia, by the concomitant use of drugs (NSAIDs), platelet inhibitors or anti-coagulants and by traumatic or repeated epidural or spinal puncture.
In decision-making on the interval between the last administration of Fragmin at prophylactic doses and the placement or removal of a peridural or spinal catheter for anaesthesia, the product characteristics and the patient profile should be taken into account. Readministration should be delayed until at least four hours after the surgical procedure is completed.
Should a physician, as a clinical judgement, decide to administer anticoagulation in the context of peridual 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.
Paediatric Patients:
Clinical experience of treatment of children is limited. If dalteparin is used in children the anti-Xa levels should be monitored.
The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome” (see section 4.6 pregnancy and lactation).
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The possibility of the following interactions with Fragmin should be considered:
i) An enhancement of the anticoagulant effect by anticoagulant/antiplatelet agents e.g. aspirin/dipyridamole, GP IIb/IIIa receptor antagonists, Vitamin K antagonists, NSAIDs e.g. indometacin, cytostatics, dextran, thrombolytics, sulfinpyrazone, probenecid, and etacrynic acid.
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 vasodilatatory 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.
As heparin has been shown to interact with intravenous nitroglycerine, high dose penicillin, quinine and tobacco smoking interaction cannot be ruled out for dalteparin.
4.6 Pregnancy And Lactation
Pregnancy
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal developments, parturition or postnatal development (see Section 5.3 Preclinical Safety Data).
Only very limited controlled studies are so far available on the use of low molecular heparins in pregnancy. Dalteparin does not pass the placenta.
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 (see Section 5.3 Preclinical Safety Data).
Therefore, caution should be exercised when prescribing to pregnant women. Epidural anaesthesia during childbirth is absolutely contraindicated in women who are being treated with high-dose anticoagulants (see section 4.3). In pregnant women during the last trimester, dalteparin anti-Xa half-lives of 4 to 5 hours were measured.
Fragmin 25000 IU/ml, solution for injection, solution, contain benzyl alcohol as a preservative. As benzyl alcohol may cross the placenta, Fragmin without preservative should therefore be used during pregnancy (see section 4.4 warnings and precautions).
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.
Lactation
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 levelsin breast milk, equivalent to a milk/plasma ratio of <0.025-0.224. As oral absorption of low molecular weight heparin is extremely low the clinical implications, if any, of this small amount of anticoagulant activity on the nursing infant are unknown.
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.
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).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse events associated with dalteparin therapy, in patients participating in controlled clinical studies were:
System Organ Class
|
Frequency
|
Adverse Reactions
|
Blood and lymphatic system disorders
|
Common
Rare
|
Reversible Mild non-immunologically-mediated thrombocytopenia (type I)
Haemorrhage
Immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications – arterial and/or thrombosis or thromboembolism)
|
Immune system disorders
|
Rare
|
Allergic reactions
|
Endocrine disorders
|
Uncommon
|
Hyperkalaemia
|
Vascular disorders
|
Common
|
Haemorrhage (bleeding at any site)
|
Hepatic and biliary disorders
|
Common
|
Transient elevation of liver transaminases (ASAT, ALAT)
|
Skin and subcutaneous tissue disorders
|
Uncommon
Rare
|
Urticaria, pruritus
Skin necrosis, transient alopecia
|
General disorders and administration site conditions
|
Uncommon
Common
|
Pain at injection site,
Subcutaneous haematoma at injection site
|
In post-marketing experience, the following additional undesirable effects have been reported:
System Organ Class
|
Undesirable Effects
|
Immune system disorders
|
Anaphylactic reactions
|
Endocrine Disorders
|
Hypoaldosteronism
|
Nervous system disorders
|
Intracranial bleeds have been reported and some have been fatal
|
Cardiac Disorders
|
Prosthetic cardiac valve thrombosis
|
Vascular Disorders
|
Haemorrhage (bleeding at any site), some cases reported have been fatal
|
Gastrointestinal disorders
|
Retroperitoneal bleeds have been reported and some have been fatal
|
Injury, poisoning and procedural complications
|
Spinal or epidural haematoma
|
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 Special warnings and precautions for use).
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.
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Dalteparin sodium is a low molecular weight heparin fraction (average molecular weight 4000-6000 daltons) produced from porcine-derived sodium heparin.
Dalteparin sodium is an antithrombotic agent, which acts mainly through its ability to potentiate the inhibition of Factor Xa and thrombin by antithrombin. It has a relatively higher ability to potentiate Factor Xa inhibition than to prolong plasma clotting time (APTT)
Compared with standard, unfractionated heparin, dalteparin sodium has a reduced adverse effect on platelet function and platelet adhesion, and thus has only a minimal effect on primary haemostasis. Still some of the antithrombotic properties of dalteparin sodium are thought to be mediated through the effects on vessel walls or the fibrinolytic system.
In a randomised, actively controlled, double –blind trial in 1500 patients undergoing hip replacement surgery ( North American Fragmin Trial), both pre-operative and post operative Fragmin were found to be superior to warfarin ( see table below). There was a numerical superiority for pre-operative Fragmin over post-operative Fragmin. Thus in patients where the risk of bleeding is perceived to be too great for pre-operative Fragmin administration other means of reducing thromboembolic risk such as post-operative Fragmin administration may be considered.
Incidence of verified thromboembolic events in ITT efficacy population within 6 ± 2 post operative days
Phase 1
|
Pre-op Dalteparin
|
Post-op Dalteparin
|
Warfarin
|
|
|
|
|
n/N
|
%
|
n/N
|
%
|
n/N
|
%
|
DVT and or PE
|
37/338*
|
10.9
|
44/336*
|
13.1
|
81/338
|
24.0
|
Proximal DVT
|
3/354
|
0.8
|
3/358
|
0.8
|
11/363
|
3.0
|
*p 0.001 vs warfarin ( Cocharan-Mantel-Haenszel test, two-sided)
Abbreviations : n/N = number of patients affected/number of efficacy-evaluable patients; post-op = treatment at earliest 4 hours after surgery;
Pre-op, = treatment within 2 hours before surgery
In a randomised; placebo-controlled double-blind trial (PREVENT) in 3700 patients with acute medical conditions requiring a projected stay in hospital of>4 days and with recent (<3 days) immobilisation (defined as patients mainly confined to bed during waking hours), the incidence of clinically relevant thromboembolic events was reduced by 45% in patients randomised to receive Fragmin compared with those who received placebo. The incidence of the events comprising the primary endpoint was 2.77% compared with 4.96% in placebo treated patients (difference: - 2.19; 95% CI: - 3.57 to - 0.81; p=0.0015. Therefore, a clinically meaningful reduction in the risk of venous thromboembolism was seen in this study.
5.2 Pharmacokinetic Properties
The half-life following i.v. and s.c. administration is 2 hours and 3.5-4 hours respectively, twice that of unfractionated heparin.
The bioavailability following s.c. injection is approximately 87 per cent and the pharmacokinetics are not dose dependent. The half life is prolonged in uraemic patients as dalteparin sodium is eliminated primarily through the kidneys.
Special Populations
Haemodialysis:
In patients with chronic renal insufficiency requiring haemodialysis, the mean terminal hal-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers; therefore, greater accumulation can be expected in these patients.
5.3 Preclinical Safety Data
The acute toxicity of dalteparin sodium is considerably lower than that of heparin. The only significant finding, which occurred consistently throughout the toxicity studies after subcutaneous administration of the higher dose levels was local haemorrhage at the injection sites, dose-related in incidence and severity. There was no cumulative effect on injection site haemorrhages.
The haemorrhagic reaction was reflected in dose related changes in the anticoagulant effects as measured by APTT and anti-Factor Xa activities.
It was concluded that dalteparin sodium did not have a greater osteopenic effect than heparin since at equivalent doses the osteopenic effect was comparable.
The results revealed no organ toxicity irrespective of the route of administration, doses or duration of treatment. No mutagenic effect was found. No embryotoxic or teratogenic effects and no effect on fertility, reproductive capacity or peri- and post natal development was shown.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium Chloride (Ph.Eur)
(2,500 IU presentation only)
Water for Injections (Ph. Eur.)
(2,500IU and 5,000IU presentations)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
36 months
6.4 Special Precautions For Storage
Do not store above 25°C
6.5 Nature And Contents Of Container
Single dose syringe (glass Ph. Eur. Type I) with chlorobutyl rubber stopper containing dalteparin sodium 2500 IU (anti-Factor Xa) in 0.2 ml
Single dose syringe (glass Ph. Eur. Type I) with chlorobutyl rubber stopper containing dalteparin sodium 5000 IU (anti-Factor Xa) in 0.2 ml.
6.6 Special Precautions For Disposal And Other Handling
Not applicable
7. Marketing Authorisation Holder
Pfizer Limited
Ramsgate Road
Sandwich KENT
CT13 9NJ
United Kingdom
8. Marketing Authorisation Number(S)
Fragmin 2500 IU :PL 00057/0983
Fragmin 5000 IU :PL 00057/0984
9. Date Of First Authorisation/Renewal Of The Authorisation
18 March 2002
10. Date Of Revision Of The Text
August 2010
LEGAL CATEGORY
POM
Ref: FR 8_0
