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FRAGMIN Solution for Injection

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

FRAGMIN Solution for Injection

FRAGMIN 2 500 IU/0,2 mL Solution for Injection (0,5 mL Single dose syringes)
FRAGMIN 5 000 IU/0,2 mL Solution for Injection (0,5 mL Single dose syringes)
FRAGMIN 2 500 IU/mL Solution for Injection (4 mL Ampoule)
FRAGMIN 10 000 IU/mL Solution for Injection (1 mL Graduated syringe)
FRAGMIN 25 000 IU/mL Solution for Injection (4 mL Vial)
FRAGMIN 10 000 IU/0,4 mL Solution for Injection (1 mL Single dose syringe)
FRAGMIN 12 500 IU/0,5 mL Solution for Injection (1 mL Single dose syringe)
FRAGMIN 15 000 IU/0,6 mL Solution for Injection (1 mL Single dose syringe)
FRAGMIN 18 000 IU/0,72 mL Solution for Injection (1 mL Single dose syringe)

COMPOSITION:

FRAGMIN 2 500 IU/0,2 mL:	Each 0,2 mL contains dalteparin sodium 2 500 IU (anti-factor Xa)
FRAGMIN 5 000 IU/0,2 mL:	Each 0,2 mL contains dalteparin sodium 5 000 IU (anti-factor Xa)
FRAGMIN 2 500 IU/mL:	Each 1 mL contains dalteparin sodium 2 500 IU (anti-factor Xa)
FRAGMIN 10 000 IU/mL:	Each 1 mL contains dalteparin sodium 10 000 IU (anti-factor Xa)
FRAGMIN 25 000 IU/mL:	Each 1 mL contains dalteparin sodium 25 000 IU (anti-factor Xa) and 1,4% m/v benzyl alcohol as preservative
FRAGMIN 10 000 IU/0,4 mL:	Each 0,4 mL contains dalteparin sodium 10 000 IU (anti-factor Xa)
FRAGMIN 12 500 IU/0,5 mL:	Each 0,5 mL contains dalteparin sodium 12 500 IU (anti-factor Xa)
FRAGMIN 15 000 IU/0,6 mL:	Each 0,6 mL contains dalteparin sodium 15 000 IU (anti-factor Xa)
FRAGMIN 18 000 IU/0,72 mL:	Each 0,72 mL contains dalteparin sodium 18 000 IU (anti-factor Xa)

PHARMACOLOGICAL CLASSIFICATION:
A 8.2 Anticoagulants

PHARMACOLOGICAL ACTION:
FRAGMIN is an antithrombotic agent containing dalteparin sodium. Dalteparin sodium is the sodium salt of low molecular mass heparin extracted from pork intestinal mucosa and is manufactured by controlled depolymerization of heparin. FRAGMIN consists of strongly acidic sulphated polysaccharide chains which have an average molecular mass of about 5 000. The antithrombotic effect of FRAGMIN is dependent on its ability to potentiate the inhibition of Factor Xa and thrombin by antithrombin (AT).
FRAGMIN has a relatively higher ability to potentiate Factor Xa inhibition than to prolong plasma clotting time (APTT). FRAGMIN has less effect on platelet function and platelet adhesion than heparin, and thus has only a slight effect on primary haemostasis.
Some of the antithrombotic properties of dalteparin sodium are, however, thought to be mediated through the effect on vessel wall or the fibrinolytic system.
The half-life after i.v. injection is 2 hours and after s.c. injection 3 - 4 hours. The bioavailability is approximately 90%after s.c. injection and the plasma half-life of FRAGMIN anti-Factor Xa activity is non-dose dependent within the therapeutic intervals.
Maximum anticoagulant effect is achieved within one to two minutes after i.v. injection.
Dalteparin sodium is eliminated primarily through the kidneys.
The pharmacokinetics of FRAGMIN in the elderly is similar to that in younger persons.

INDICATIONS:

1.	Treatment of acute deep venous thrombosis.
2.	Prevention of clotting in the extra-corporeal system during haemodialysis and haemofiltration in connection with acute renal failure or chronic renal insufficiency.
3.	Prophylaxis against deep venous thrombosis, which may lead to pulmonary embolism, in patients undergoing orthopaedic, abdominal or gynaecological surgery who are at risk for thromboembolic complications. Patients with a moderate risk include patients who are over 40 years of age and/or obese, undergoing surgery under general anaesthesia lasting longer than 30 minutes, or high risk patients such as patients with malignancy, or patients undergoing orthopaedic surgery.
4.	Unstable coronary artery disease i.e. unstable angina and non-Q-wave myocardial infarction.

CONTRA-INDICATIONS:
Hypersensitivity to dalteparin sodium or other low molecular mass heparins and/or heparins.
History of confirmed or suspected immunologically-mediated heparin-induced thrombocytopenia.
Cerebral haemorrhage and haemorrhagic stroke.
Severe uncontrolled hypertension.
Severe coagulation disorders.
Infective endocarditis.
Peptic ulcer.
Threatened abortion.
Known haemorrhagic diathesis.

FRAGMIN should not be given to patients undergoing surgery or who have injuries of the brain, eye, ear or spinal cord or who are undergoing lumbar puncture, including epidural or spinal anaesthesia.

Regional anaesthesia in conjunction with treatment of acute deep venous thrombosis and unstable coronary artery disease due to increased risk of bleeding.

WARNINGS:
Do not administer by the intramuscular route.
Individual low molecular mass heparins have differing characteristics and different dosages are administered. Particular caution is therefore required and the directions for use relating to each specific product must be observed.
When neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal puncture is employed, patients scheduled to be on FRAGMINare at risk of developing an epidural or spinal haematoma, which can result in long-term or permanent paralysis.
The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting haemostasis 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. If neurological compromise is noted, urgent treatment (decompression) is necessary.
The physician should consider the potential benefit versus the risk before neuraxial intervention in patients anticoagulated for thromboprophylaxis.

DOSAGE AND DIRECTIONS FOR USE:

1.

Treatment of acute deep venous thrombosis.

200 IU/kg body weight is administered s.c. once daily. Monitoring of the anticoagulant effect is not necessary. The single daily dose should not exceed 18 000 IU. 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.

The dosage may be adjusted to the single-dose syringes as in the table below:

Weight (kg)	Dose	Single dose syringe
46-56	10 000 IU	0,4 mL
57-68	12 500 IU	0,5 mL
69-82	15 000 IU	0,6 mL
83 or over	18 000 IU	0,72 mL

2.	Prevention of clotting during haemodialysis and haemofiltration:
2a.	Chronic renal failure, patients with no known bleeding risk.
	Haemodialysis and haemofiltration for a maximum of 4 hours:
	Dose as below or as an intravenous bolus injection of 5 000 IU only.
	Haemodialysis and haemofiltration for more than 4 hours:
	Intravenous bolus injection of 30 - 40 IU/kg body weight followed by an intravenous infusion of 10 - 15 IU/kg body weight per hour. Administered doses normally produce a plasma level lying within the range of 0,5 - 1,0 IU anti-Xa/mL.
2b.	Acute renal failure, patients with high bleeding risk:
	Intravenous bolus injection of 5 - 10 IU/kg body weight, followed by intravenous infusion of 4 - 5 IU/kg body weight per hour. Plasma levels should lie within the range of 0,2 - 0,4 IU anti-Xa/mL.
3.	Thromboprophylaxis:
3a.	Surgical thromboprophylaxis in patients at moderate risk of thrombosis:
	Patients undergoing abdominal and gynaecological surgery with a moderate risk for thromboembolic complications:
	2 500 IU administered subcutaneously 1 - 2 hours before the operation and thereafter 2 500 IU subcutaneously each morning until the patient is mobilized, in general 5 to 7 days or longer.
3b.	Surgical thromboprophylaxis in patients at high risk of thrombosis:
	High risk patients such as patients undergoing orthopaedic surgery or patients with a malignancy undergoing abdominal or gynaecological surgery:
	5 000 IU is given subcutaneously the evening before operation and 5 000 IU subcutaneously the following evenings. Treatment is continued until the patient is mobilised, in general 5 to 7 days or longer.
	As an alternative 2 500 IU is given subcutaneously 1 - 2 hours before the operation and 2 500 IU subcutaneously 8 - 12 hours later. On the following days 5 000 IU is given subcutaneously each morning. Treatment is continued until the patient is mobilised, in general 5 to 7 days or longer.
3c.	Prolonged thromboprophylaxis in hip replacement surgery:
	5 000 IU is given subcutaneously the evening before the operation and 5 000 IU subcutaneously the following evenings. Treatment is continued for five post-operative weeks. As an alternative 2 500 IU is given subcutaneously 1 - 2 hours before the operation and 2 500 IU subcutaneously 8 - 12 hours later. On the following days 5 000 IU is given subcutaneously each morning for five post-operative weeks.
4.	Unstable coronary artery disease, i.e. unstable angina and non-Q-wave myocardial infarction:
	120 IU/kg body weight is administered subcutaneously twice daily. The maximum dose is 10 000 IU/12 hours.
	Treatment should be continued for at least 6 days or longer if considered of benefit by the physician.
	For patients awaiting revascularisation, FRAGMIN is recommended to be given until day of invasive procedure (PTCA or CABG). After an initial stabilisation for 5 –7 days with a body weight adjusted dose of 120 IU/kg/b.w. twice daily, FRAGMIN will be given at a fixed dose of 5 000 IU (women <80 kg and men <70 kg) or 7 500 IU (women = 80 kg and men = 70 kg) twice daily. The total treatment period should not exceed 45 days.
	Concomitant therapy with low dose acetylsalicylic acid is recommended.

Summary: Suitability of dosage forms:
Ampoules/vials/graduated syringe:
Solution for injection for intravenous or subcutaneous administration:

	10 000 IU/mL in a graduated syringe containing 1 mL.
	2 500 IU/mL in an ampoule containing 4 mL.
	25 000 IU/mL in a vial containing 4 mL (with benzyl alcohol).

Single dose syringes:
Solution for injection for subcutaneous administration in prefilled single dose syringes:

	2 500 IU per 0,2 mL
	5 000 IU per 0,2 mL
	10 000 IU per 0,4 mL
	12 500 IU per 0,5 mL
	15 000 IU per 0,6 mL
	18 000 IU per 0,72 mL

Compatibility:
FRAGMIN is compatible with isotonic sodium chloride (0,9%) and isotonic glucose (5%) infusion solutions in glass bottles and plastic containers.
The solution should be used within twelvehours.
Compatibility between FRAGMIN and other products has not been investigated.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Bleeding may be provoked, especially following high doses.
Subcutaneous haematomas at the injection site may occur.
Thrombocytopenia, either reversible or severe and potentially fatal, may occur; the latter is associated with arterial and/or venous thrombosis or thromboembolism.
Skin necrosis, allergic reactions and bleeding complications have been reported.
Transient, slight to moderate, elevation of liver transaminases (ASAT, ALAT) has been observed.
Anaphylactoid reactions have been observed.
As FRAGMIN is derived from heparin, a risk of osteoporosis following long-term use cannot be ruled out.
Precautions:
Caution is recommended in patients with thrombocytopenia and platelet defects,severe hepatic and renal impairment, uncontrolled hypertension, and hypertensive or diabetic retinopathy.
Care should also be taken when administering high doses of FRAGMIN to newly-operated patients.
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/microL) associated with positive or unknown results of in vitro tests for antiplatelet antibody in the presence of FRAGMIN or other low molecular mass heparins and/or heparins.
When administered in a dose of 2 500 to 5 000 IU (anti-Factor Xa)/day, FRAGMIN does not generally accumulate. However, chromogenic substrate assays can be used to measure anti-Factor Xa activity. 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.
For laboratory monitoring of FRAGMIN, anti-Factor Xa levels should be used.
Patients undergoing chronic haemodialysis with FRAGMIN normally require only a few dose adjustments and therefore only a few checks of anti-Xa levels.
Patients undergoing acute haemodialysis have a narrower therapeutic dosage range and should be subjected to comprehensive monitoring of anti-Xa levels.
If a transmural myocardial infarction occurs in patients with unstable coronary artery disease, i.e. unstable angina and non-Q-wave myocardial infarction, thrombolytic treatment might be appropriate.
This does not necessitate discontinuation of treatment with FRAGMIN but might increase the risk of bleeding.
Use in pregnancy and lactation:
Use of FRAGMIN during pregnancy has been assessed and there is no evidence of dalteparin sodium crossing the placental barrier. No harmful effects are known with respect to the course of pregnancy and the health of the unborn and neonate.
No information is available as to whether FRAGMIN passes into breast milk.
The solution for injection with preservative should however not be used during pregnancy, since it contains benzyl alcohol, which may pass the placenta.
One should bear in mind the potential toxicity for premature infants after administration of benzyl alcohol.
Interactions:
Concomitant medication with effect on haemostasis such as aspirin, vitamin K antagonists, NSAIDs and dextran, may enhance the anticoagulant effect of FRAGMIN.
However, unless specifically contra-indicated, patients with unstable coronary artery disease, i.e. unstable angina and non-Q-wave myocardial infarction, should receive oral low dose acetylsalicylic acid.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF TREATMENT:
Overdosage with FRAGMIN may result in severe bleeding which can be inhibited by protamine.
The induced prolongation of the clotting time is fully neutralized but the anti-Xa activity is only neutralized to about 25 - 50%. 1 mg of protamine inhibits the effect of 100 anti-Xa units of dalteparin sodium.
Protamine in itself has an inhibiting effect on the primary haemostasis and should only be used in an emergency.

IDENTIFICATION:
Clear, colourless or straw-coloured solution practically free from particles.

PRESENTATION:
FRAGMIN 2 500 IU/0,2 mL Solution for Injection (0,5 mL Single dose syringe):
        Cartons containing 10 x 0,5 mL single dose syringes.
FRAGMIN 5 000 IU/0,2 mL Solution for Injection (0,5 mL Single dose syringe):
        Cartons containing 10 x 0,5 mL single dose syringes.
FRAGMIN 2 500 IU/mL Solution for Injection (4 mL Ampoule):
        Cartons containing 10 x 4 mL clear glass ampoules.
FRAGMIN 10 000 IU/mL Solution for Injection (1 mL Graduated syringe):
        Cartons containing 10 x 1 mL clear glass syringes.
FRAGMIN 25 000 IU/mL Solution for Injection (4 mL Vial):
        Cartons containing 1 x 4 mL clear glass vials.
FRAGMIN 10 000 IU/0,4 mL Solution for Injection (1 mL Single dose syringe):
        Cartons containing 5 x 1 mL clear glass single dose syringes.
FRAGMIN 12 500 IU/0,5 mL Solution for Injection (1 mL Single dose syringe):
        Cartons containing 5 x 1 mL clear glass single dose syringes.
FRAGMIN 15 000 IU/0,6 mL Solution for Injection (1 mL Single dose syringe):
        Cartons containing 5 x 1 mL clear glass single dose syringes.
FRAGMIN 18 000 IU/0,72 mL Solution for Injection (1 mL Single dose syringe):
        Cartons containing 5 x 1 mL clear glass single dose syringes.

STORAGE INSTRUCTIONS:
Store below 25°C. Do not refrigerate.
FRAGMIN 25 000 IU/mL (multidose vial) can be stored up to 14 days at room temperature below 25°C after the first penetration of the stopper.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
FRAGMIN 2 500 IU/0,2 mLSolution for Injection (0,5 mL Single dose syringe): X/8.2/87
FRAGMIN 5 000 IU/0,2 mL Solution for Injection (0,5 mL Single dose syringe): X/8.2/88
FRAGMIN 2 500 IU/mL Solution for Injection (4 mL Ampoule): X/8.2/89
FRAGMIN 10 000 IU/mL Solution for Injection (1 mL Graduated syringe): X/8.2/90
FRAGMIN 25 000 IU/mL Solution for Injection (4 mL Vial): 30/8.2/0251
FRAGMIN 10 000 IU/0,4 mL Solution for Injection (1 mL Single dose syringe): 32/8.2/0471
FRAGMIN 12 500 IU/0,5 mL Solution for Injection (1 mL Single dose syringe): 32/8.2/0472
FRAGMIN 15 000 IU/0,6 mL Solution for Injection (1 mL Single dose syringe): 32/8.2/0473
FRAGMIN 18 000 IU/0,72 mL Solution for Injection (1 mL Single dose syringe:) 32/8.2/0474

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Limited
Alphen West G
George St
Midrand
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
15 August 2001


New addition to this site: February 2005
Source: Pharmaceutical Industry
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