- dalteparin sodium
POM: Prescription only medicine
This information is intended for use by health professionals
Active ingredientDalteparin sodium (INN)Quality according to Ph. Eur.Potency is described in International anti-Factor Xa units (IU) of the 1st International Standard for Low Molecular Weight Heparin.
Content of active ingredientFragmin 100,000 IU/4 ml: Multidose vial containing dalteparin sodium corresponding to 25,000 IU (anti-Factor Xa)/ml.
Recommended dosage for adultsTreatment of venous thromboembolism (VTE).Fragmin can be administered subcutaneously either as a single daily injection or as twice daily injections.(a) Once daily administration200 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.(b) Twice daily administrationA dose of 100 IU/kg body weight administered s.c twice daily can be used for patients with increased risk of bleeding. Monitoring of the treatment is generally not necessary but can be performed with a functional anti-Factor Xa assay. Maximum plasma levels are obtained 3-4 hours after s.c injection, when samples should be taken. Recommended plasma levels are between 0.5-1.0 IU (anti-Factor 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.
Paediatric populationThe safety and efficacy of dalteparin sodium in children has not been established. Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.
Monitoring Anti-Xa levels in childrenMeasurement of peak anti-Xa levels at about 4 hours post-dose should be considered for certain special populations receiving Fragmin, such as children. For therapeutic treatment with doses administered once daily, peak anti-Xa levels should generally be maintained between 0.5 and 1.0 IU/mL measured at 4 hours post-dose. In the case of low and changing physiologic renal function such as in neonates, close monitoring of anti-Xa levels is warranted. For prophylaxis treatment the anti- Xa levels should generally be maintained between 0.2-0.4 IU/mL. 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.
ElderlyFragmin has been used safely in elderly patients without the need for dosage adjustment.
Monitoring Anti-Xa LevelsMonitoring 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 anticoagulantsDalteparin 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.
PregnancyThe 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 neededHeparin 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 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 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: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).Benzyl alcohol containing formulations must not be used in premature or newborn babies. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old (see section 6.1). Other formulations without benzyl alcohol are available.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.
PregnancyDalteparin 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.Fragmin 100000 IU/4ml multidose vial contains 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).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-feedingLimited 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.Fragmin multidose vial contains benzyl alcohol as a preservative and is not recommended for use during pregnancy. Benzyl alcohol may cross the placenta. One should bear in mind the potential toxicity for premature infants. Medications containing benzyl alcohol - (see section 4.4)
FertilityBased on current clinical data there is no evidence that dalteparin sodium effects fertility. No effects on fertility, copulation or peri- and postnatal development were noted when dalteparin sodium was tested in animals.
|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|
|Nervous system disorders||Not Known*||Intracranial bleeds have been reported and some have been fatal|
|Cardiac disorders||Not Known*||Prosthetic cardiac valve thrombosis|
|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|
|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|
Paediatric populationFrequency, 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.
|Trial design||Patients||Diagnosis||Indication, Fragmin Dose, Target anti-Xa, Duration|
|Single-center, open label trial; (n = 48)||Age: 31 week preterm to 18 years Gender: 32 males, 16 females||Arterial or venous thrombosis; PVOD; PPH||Prophylaxis: (n = 10) 95 ± 52 anti-Xa IU/kg sc qd; 0.2 to 0.4 IU/mL 3-6 months||Primary Therapy: (n = 25) 129 ± 43 anti-Xa IU/kg sc qd; 0.4 to 1.0 IU/mL 3-6 months||Secondary Therapy: (n = 13) 129 ± 43 anti-Xa IU/kg sc qd; 0.4 to 1.0 IU/mL 3-6 months|
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.
Paediatric Population:Infants less than approximately 2 to 3 months of age or < 5 kg have increased LMWH requirements per kg likely due to their larger volume of distribution. Alternative explanations for the increased requirement of LMWH per body weight in young children include altered heparin pharmacokinetics and/or a decreased expression of anticoagulant activity of heparin in children due to decreased plasma concentrations of antithrombin.
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