FRAGMIN 2500 I.U 0.2 ML

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
DALTEPARIN SODIUM
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
B01AB04
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
DALTEPARIN SODIUM 2500 IU / 0.2 ML
Administration route:
I.V, S.C
Prescription type:
Required
Manufactured by:
PFIZER MANUFACTURING BELGIUM NV/SA
Therapeutic group:
DALTEPARIN
Therapeutic area:
DALTEPARIN
Therapeutic indications:
Prevention of clotting during haemodialysis and haemofiltration in connection with acute renal failure or chronic renal insufficiency. Treatment of acute deep venous thrombosis and/or pulmonary embolism. Unstable coronary artery disease. Thromboprophylaxis in conjunction with surgery. Prophylaxis in patients with substantially increased risk for venous thromboembolism and that are temporarily immobilized due to acute illness such as cardiac insufficiency respiratory insufficiency and severe infections.Cancer patients : Treatment and secondary prevention of deep-vein thrombosis and/or pulmonary embolism.
Authorization number:
123 11 26544 00
Authorization date:
2011-08-31

FRAGMIN

®

Solution for Injection

Presentation:

Ampoules of 2,500 IU (anti-Xa)/ml (4 ml) and ampoules of 10,000 IU (anti-Xa)/ml (1 ml).

Single dose syringe of 2,500 IU (anti-Xa)/0.2 ml. 5,000 IU (anti-Xa)/0.2 ml, 7,500 IU/0.3 ml,

10,000 IU/0.4 ml, 12,500 IU/0.5 ml, 15,000 IU/0.6 ml, 18,000 IU/0.72 ml.

Composition:

1 ml solution for injection contains:

Dalteparin sodium 2,500 IU (anti-Xa); 10,000 IU (anti-Xa);

12,500 IU (anti-Xa); 25,000 IU (anti-Xa)

Sodium chloride q.s.

Sodium hydroxide or hydrochloric acid q.s.

Water for Injections ad. 1 ml.

Potency is described in international anti-Xa units (IU) of the 1st International Standard for

Low Molecular Mass Heparin.

Indications:

Treatment of acute deep venous thrombosis and/or pulmonary embolism.

Prevention of clotting during hemodialysis and hemofiltration in connection with acute

renal failure or chronic renal insufficiency.

Thromboprophylaxis in conjunction with surgery.

Unstable coronary artery disease.

Prophylaxis in patients with substantially increased risk for venous thromboembolism

and that are temporarily immobilized due to acute illness such as cardiac insufficiency,

respiratory insufficiency and severe infections.

Cancer patients: Treatment and secondary prevention of deep-vein thrombosis and/or

pulmonary embolism.

Contraindications:

Hypersensitivity to dalteparin, or other low molecular weight heparins, or heparins, or pork

products.

Confirmed or suspected history of immunologically mediated heparin induced

thrombocytopenia.

Active, clinically-significant bleeding (such as gastrointestinal ulceration or bleeding, or

cerebral hemorrhage).

Severe coagulation disorders.

Septic endocarditis.

Recent injury to, or surgical procedures of, the central nervous system, eyes and/or ears.

Because of an increased risk of bleeding, high doses of dalteparin (such as those needed

to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery

disease) should not be used in patients who will receive spinal or epidural anesthesia or

other procedures requiring spinal puncture (see section Special warnings and precautions

for use).

Pregnancy and lactation:

Pregnancy

If dalteparin is used during pregnancy, the possibility of fetal 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 Preclinical safety data).

Medications containing benzyl alcohol

(See section Special warnings and precautions for use - Pediatric patients).

Lactation

Limited data are available for excretion of dalteparin in human milk. One study in 15 lactating

women receiving prophylactic doses of dalteparin detected small amounts of anti-Xa activity

in 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.

Undesirable effects:

Clinical trials

The most frequent (≥1%) adverse events associated with dalteparin therapy, in patients

participating in controlled clinical studies were:

Blood and lymphatic system disorders: reversible non-immunologically-mediated

thrombocytopenia (type I)

Immune system disorders: allergic reactions

Vascular disorders: hemorrhage (bleeding at any site)

Hepatobiliary disorders: transient elevation of liver transaminases (ASAT, ALAT)

General disorders and administration site conditions: hematoma at injection site, pain at

injection site

In post-marketing experience, the following additional undesirable effects have

been reported:

Blood and lymphatic system disorders: immunologically-mediated heparin-induced

thrombocytopenia (type II, with or without associated thrombotic complications)

Immune system disorders: anaphylactic reactions

Nervous system disorders: intracranial bleeds have been reported and some have been fatal.

Gastrointestinal disorders: retroperitoneal bleeds have been reported and some have been fatal.

Skin and subcutaneous tissue disorders: skin necrosis, alopecia, rash

Injury, poisoning and procedural complications: spinal or epidural hematoma (see section

Contraindications and section Special warnings and precautions for use).

Vascular disorders: hemorrhage (bleeding at any site), some cases reported have been fatal.

Posology and method of administration:

See section Special warnings and precautions for use.

General

DO NOT ADMINISTER DALTEPARIN BY THE INTRAMUSCULAR ROUTE.

Compatibility with IV solutions

Dalteparin is compatible with isotonic sodium chloride (9 mg/ml) or isotonic glucose

(50 mg/ml) infusion solution in glass bottles and plastic containers.

Treatment of acute deep venous thrombosis and pulmonary embolism

Fragmin

can be administered subcutaneously either as a single daily injection or as two

daily injections.

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.

Twice daily administration:

Alternatively, a dose of 100 IU/kg total body weight administered SC twice daily may be given.

Monitoring of the anticoagulant effect is generally not necessary but should be considered

for specific patient populations (see section Special warnings and precautions for use).

Maximum plasma levels are obtained 3-4 hours after SC injection when samples should be

taken. Recommended plasma levels are between 0.5-1.0 IU anti-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.

Outpatient treatment is feasible using the same doses recommended for treatment in a

medical institution.

Prevention of clotting during hemodialysis and hemofiltration

Administer dalteparin intravenously (IV), selecting the appropriate regimen from those

described below.

Patients with chronic renal insufficiency or patients with no known risk of bleeding:

These patients normally require few dose adjustments, and therefore frequent monitoring

of anti-Xa levels is not necessary for most patients. Recommended doses usually produce

plasma levels between 0.5 to 1.0 IU anti-Xa/ml during dialysis.

Hemodialysis and hemofiltration up to a maximum of 4 hours:

Either 30 to 40 IU/kg total body weight IV bolus injection followed by 10 to 15 IU/kg/hour

IV infusion, or a single IV bolus injection of 5,000 IU.

Hemodialysis and hemofiltration longer than 4 hours:

Administer 30 to 40 IU/kg total body weight IV bolus injection, followed by 10 to 15 IU/kg/

hour IV infusion.

Patients with acute renal failure or patients with high risk of bleeding:

Administer 5 to 10 IU/kg total body weight as IV bolus injection, followed by 4 to 5 IU/kg/

hour IV infusion. Patients undergoing acute hemodialysis have a narrower therapeutic range

than patients on chronic hemodialysis, and should undergo comprehensive monitoring of

anti-Xa levels. Recommended plasma levels are between 0.2 to 0.4 IU anti-Xa/ml.

Thromboprophylaxis in conjunction with surgery

Administer dalteparin subcutaneously (SC). Monitoring of the anticoagulant effect is generally

not necessary. If done, samples should be taken during maximum plasma levels (3 to 4 hours

after an SC injection). Recommended doses usually produce peak plasma levels between

0.1 and 0.4 IU anti-Xa/ml.

General surgery:

Select the appropriate regimen from those listed below.

Patients at risk for thromboembolic complications:

2,500 IU SC within 2 hours before surgery and 2500 IU SC each postoperative morning

until the patient is mobilized (generally 5 to 7 days or longer).

Patients with additional risk factors for thromboembolism (e.g., malignancy):

Administer dalteparin until the patient is mobilized (generally 5 to 7 days or longer).

Start on day before surgery - 5,000 IU SC on the evening before surgery. Following

surgery, 5,000 IU SC each evening.

Start on day of surgery - 2,500 IU SC within 2 hours before surgery and 2,500 IU SC

8 to 12 hours later, but no sooner than 4 hours after the end of surgery. Starting on the

day after surgery, 5,000 IU SC each morning.

Orthopedic surgery (such as hip replacement surgery):

Administer dalteparin for up to 5 weeks after surgery, selecting one of the regimens listed

below.

Preoperative start: Evening before surgery - 5,000 IU SC on the evening before surgery.

Following surgery, 5,000 IU SC each evening.

Preoperative start: Day of surgery - 2,500 IU SC within 2 hours before surgery and

2,500 IU SC 8 to 12 hours later, but no sooner than 4 hours after the end of surgery.

Starting on the day after surgery, 5,000 IU SC each morning.

Postoperative start - 2,500 IU SC 4 to 8 hours after surgery, but no sooner than 4 hours

after the end of surgery. Starting on the day after surgery, 5,000 IU SC each day.

Thromboprophylaxis in patients with restricted mobility

Administer 5,000 IU of dalteparin subcutaneously (SC) once daily, generally for 12 to 14

days or longer in patients with continued restricted mobility. Monitoring of the anticoagulant

effect is generally not necessary.

Unstable coronary artery disease (unstable angina and non-ST-elevation myocardial

infarction

Administer dalteparin 120 IU/kg total body weight subcutaneously (SC) every 12 hours up to

a maximum dose of 10,000 IU/12 hours. Unless specifically contraindicated, patients should

also receive concomitant therapy with acetylsalicylic acid (75 to 325 mg/day). Continue

treatment until the patient is clinically stable (generally at least 6 days), or longer if considered

of benefit by the physician.

Thereafter, extended treatment with a fixed dose of dalteparin is recommended until a

revascularization procedure is performed (such as percutaneous interventions [PCI] or

coronary artery bypass graft [CABG]). The total treatment period should not exceed 45 days.

The dose of dalteparin is selected according to the patient’s gender and weight:

FRAG INJ PHY SH 220119

For women weighing less than 80 kg and men weighing less than 70 kg, administer 5,000

IU SC every 12 hours.

For women weighing at least 80 kg and men weighing at least 70 kg, administer 7,500 IU

SC every 12 hours.

Monitoring of the anticoagulant effect is generally not necessary but should be considered

for specific patient populations (see section Special warnings and precautions for use).

Samples should be taken during maximum plasma levels (3 to 4 hours after a SC injection).

Recommended peak plasma levels are between 0.5 and 1.0 IU anti-Xa/ml.

Extended treatment of symptomatic VTE to reduce recurrence of VTE in patients

with cancer

Month 1

Administer dalteparin 200 IU/kg total body weight subcutaneously (SC) once daily for the

first 30 days of treatment. The total daily dose should not exceed 18,000 IU daily.

Months 2-6

Dalteparin should be administered at a dose of approximately 150 IU/kg subcutaneously,

once daily using fixed dose syringes and Table 1 shown below.

Table 1: Dosage determination for months 2-6

Body Weight (kg)

Dalteparin Dose (IU)

7,500

57 to 68

10,000

69 to 82

12,500

83 to 98

15,000

18,000

Dose reductions for chemotherapy-induced thrombocytopenia

Thrombocytopenia: In the case of chemotherapy-induced thrombocytopenia with platelet

counts <50,000/mm

, dalteparin should be interrupted until the platelet count recovers

above 50,000/mm

For platelet counts between 50,000 and 100,000/mm

, dalteparin should be reduced by 17%

to 33% of the initial dose depending on the patient’s weight (Table 2). Once the platelet count

recovered to ≥100,000/mm

, dalteparin should be re-instituted at full dose.

Table 2: Dose reduction of dalteparin for thrombocytopenia 50,000-100,000/mm

3

Body Weight

(kg)

Scheduled

Dalteparin Dose

(IU)

Reduced

Dalteparin Dose

(IU)

Mean Dose

Reduction

7,500

5,000

57 to 68

10,000

7,500

69 to 82

12,500

10,000

83 to 98

15,000

12,500

18,000

15,000

Renal failure

In the case of significant renal failure, defined as a creatinine level >3 x ULN, the dose of

dalteparin should be adjusted to maintain an anti-Xa therapeutic level of 1 IU/ml (range 0.5-1.5

IU/ml) measured 4-6 hours after the dalteparin injection. If the anti-Xa level is below or above

the therapeutic range, the dose of dalteparin should be increased or reduced, respectively,

by one syringe formulation and the anti-Xa measurement should be repeated after 3-4 new

doses. This dose adjustment is to be repeated until the anti-Xa therapeutic level is achieved.

Compatibility:

Fragmin

is compatible with isotonic sodium chloride (9 mg/ml) or isotonic glucose

(50 mg/ml) infusion solution in glass bottles and plastic containers. The solution should be

used within 12 hours.

Compatibility between Fragmin

and other products has not been investigated.

Special warnings and precautions for use:

Epidural or spinal anesthesia

When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed,

patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins

or heparinoids for prevention of thromboembolic complications 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 use of indwelling epidural catheters for administration

of analgesia or by the concomitant use of drugs affecting homeostasis such as non-steroidal

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 frequently monitored for signs and symptoms of neurological impairment. If

neurologic compromise is noted, urgent treatment (spinal cord decompression) is necessary

(see section 4.3 Contraindications).

Risk of hemorrhage

Dalteparin should be used with caution in patients who have a potentially higher risk of

hemorrhage, such as patients with thrombocytopenia, platelet disorders, severe liver or

kidney insufficiency, uncontrolled hypertension, or hypertensive or diabetic retinopathy.

High doses of dalteparin, such as those needed to treat deep-vein thrombosis, pulmonary

embolism, or unstable coronary artery disease, should be used with caution in patients who

had a recent surgical procedure.

Thrombocytopenia

It is recommended that the platelets be counted before the initiation of dalteparin treatment

and be followed regularly during treatment. Special caution is necessary if thrombocytopenia

develops rapidly or to a significant degree (less than 100,000/µL or mm

) during treatment

with dalteparin. In either case, an in vitro test for antiplatelet antibodies in the presence of

heparins or low molecular weight heparins is recommended. If the result of the in vitro test is

positive or inconclusive, or no test is performed, treatment with dalteparin should be stopped

(see section Contraindications).

Monitoring anti-Xa levels

Monitoring of the anticoagulant effect of dalteparin is generally not necessary but should

be considered for specific patient populations such as pediatrics; those with renal failure;

or those who are very thin or morbidly obese, pregnant, or at increased risk for bleeding or

rethrombosis. 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 Overdose).

Hyperkalemia

Heparin and low molecular weight heparin can suppress adrenal secretion of aldosterone

leading to hyperkalemia, particularly in patients such as those with diabetes mellitus, chronic

renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassium

sparing drugs. Plasma potassium should be measured in patients at risk.

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.

Osteoporosis

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.

Pediatric patients

There is limited safety and efficacy information on the use of dalteparin in pediatric patients.

If dalteparin is used in these patients, 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”. Because benzyl alcohol

may cross the placenta, [dalteparin] multiple-dose vials, preserved with benzyl alcohol,

should be used with caution in pregnant women and only if clearly needed (see section

Pregnancy and lactation).

Geriatric patients

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.

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. Any suspected

adverse events should be reported to the Ministry of Health

according to the National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.health.gov.il

Interaction with other medicinal products and other forms

of interaction:

Concomitant use of drugs affecting hemostasis, such as

thrombolytic agents, other anticoagulants, nonsteroidal

anti-inflammatory drugs, or platelet inhibitors, or dextran

may enhance the anticoagulant effect of dalteparin (see section Posology and method of

administration - Unstable coronary artery disease (unstable angina and non-ST-elevation

myocardial infarction)).

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.

Effects on ability to drive and use machines:

The effect of dalteparin on the ability to drive or use machinery has not been systematically

evaluated.

Overdose:

The anticoagulant effect induced by dalteparin sodium is inhibited by protamine. However,

protamine has an inhibiting effect on primary hemostasis and should be used only in an

emergency. A dose of 1 mg of protamine partially neutralizes the effect of 100 IU (anti-Xa) of

dalteparin (although the induced prolongation of the clotting time is fully neutralized, 25 to

50% of the anti-Xa activity of dalteparin remains).

Pharmacological properties:

Pharmacodynamic properties

The antithrombotic effect of dalteparin is due to its ability to intensify the inhibition of factor Xa

and thrombin. Dalteparin has, from the general aspect, greater ability to intensify the inhibition

of factor Xa than to prolong the time for clot formation in plasma (APTT). Dalteparin has a

relatively small effect on platelet function and platelet adhesiveness compared with heparin

and thereby a small effect on primary hemostasis.

Pharmacokinetic properties

Pharmacokinetics and metabolism

Absorption: Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa

activity, was 87 ± 6%. Increasing the dose from 2,500 to 10,000 IU resulted in an overall

increase in anti-Factor Xa AUC that was proportionally greater by about one-third.

Distribution: The volume of distribution for dalteparin anti-Factor Xa activity was 40 to 60 ml/kg.

Metabolism: Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were

2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5 hours)

are observed following SC dosing, possibly due to delayed absorption.

Excretion: Dalteparin is primarily excreted by the kidneys, however, the biological activity of

the renally eliminated fragments is not well characterized. Less than 5% of anti-Xa activity is

detectable in the urine. The mean plasma clearances of dalteparin anti-Factor Xa activity in

normal volunteers following single intravenous bolus doses of 30 and 120 anti-Factor Xa IU/

kg were 24.6 ± 5.4 and 15.6 ± 2.4 ml/hr/kg, respectively. The corresponding mean disposition

half-lives are 1.47 ± 0.3 and 2.5 ± 0.3 hours.

Special Populations

Hemodialysis: In patients with chronic renal insufficiency requiring hemodialysis, the mean

terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5,000 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.

Preclinical safety data:

Carcinogenesis, mutagenesis, impairment of fertility

Irrespective of method of administration, dose or treatment period, no organotoxicity was

noted. No mutagenic effects were noted. No embryotoxic, fetotoxic or teratogenic effects,

and no effects on fertility, copulation or peri- and postnatal development were noted when

tested in animals.

Storage:

Store below 25°C.

The expiry date of the product is indicated on the packaging materials.

Manufacturer:

Pfizer Manufacturing Belgium NV, Puurs, Belgium.

License Holder:

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725.

License Numbers:

Fragmin

2500 IU /0.2 ML

123-11-26544

Fragmin

2500 IU/ML

125-12-26545

Fragmin

10000 IU/ML

123-12-26547

Fragmin

25000 IU/ML

053-52-26546

The format of this leaflet was determined by the Ministry of Health, and its content was

checked and approved.

Similar products

Search alerts related to this product

View documents history

Share this information