Israel - English - Ministry of Health
Solution for Injection
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.
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.
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
Hypersensitivity to dalteparin, or other low molecular weight heparins, or heparins, or pork
Confirmed or suspected history of immunologically mediated heparin induced
Active, clinically-significant bleeding (such as gastrointestinal ulceration or bleeding, or
Severe coagulation disorders.
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
Pregnancy and lactation:
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).
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.
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
In post-marketing experience, the following additional undesirable effects have
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.
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
can be administered subcutaneously either as a single daily injection or as two
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
Outpatient treatment is feasible using the same doses recommended for treatment in a
Prevention of clotting during hemodialysis and hemofiltration
Administer dalteparin intravenously (IV), selecting the appropriate regimen from those
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.
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
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
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
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.
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)
57 to 68
69 to 82
83 to 98
Dose reductions for chemotherapy-induced thrombocytopenia
Thrombocytopenia: In the case of chemotherapy-induced thrombocytopenia with platelet
, dalteparin should be interrupted until the platelet count recovers
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
57 to 68
69 to 82
83 to 98
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.
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.
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).
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.
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.
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).
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
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
Interaction with other medicinal products and other forms
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
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
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).
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.
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.
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.
Store below 25°C.
The expiry date of the product is indicated on the packaging materials.
Pfizer Manufacturing Belgium NV, Puurs, Belgium.
Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725.
2500 IU /0.2 ML
The format of this leaflet was determined by the Ministry of Health, and its content was
checked and approved.