Dalteparin Sodium [Discontinued in SA Market]

Registered South African indications:

• Deep venous thrombosis
• Prevention of thrombus formation
• Unstable coronary artery disease

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• History of heparin-induced thrombocytopenia
• Acute gastroduodenal ulcer
• Cerebral haemorrhage
• Known haemorrhagic diathesis
• Active haemorrhage
• Coagulation disorder
• Acute or sub-acute septic endocarditis
• Haemorrhagic pericardial effusion
• Haemorrhagic pleural effusion
• Injuries to and operations on the central nervous system, eyes and ears
• Local and regional anaesthesia (high doses)
• Cancer patients with body weight <40kg
• Recent stroke unless due to systemic emboli

Cautions

• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• History of surgery or trauma
• Thrombocytopenia
• Defective platelet function
• Uncontrolled hypertension
• Hypertensive or diabetic retinopathy
• High doses
• Brain tumors
• Diabetes mellitus
• Metabolic acidosis
• Hyperkalaemia
• Spinal puncture
• Prosthetic heart valves
• Children
• Elderly (especially aged 80 years and above)

Forms avail. in SA and covered in this monograph: inj

Treatment of acute deep venous thrombosis

• SC: 100 IU/kg, 12hrly; Treatment duration: At least 5 days

Admin. on basis of body weight; Max single dose: 18 000 IU (eighteen thousand):

Weight (kg)	Dose (IU)
46-56	10 000
57-68	12 500
69-82	15 000
83 and over	18 000

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Simultaneous anti-coagulation with vitamin K antagonists can be started immediately

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Prevention of clotting in the extra-corporeal system during haemodialysis and haemofiltration
- Chronic renal failure with no known bleeding risk

Hemodialysis/filtration ≤4 hours

• IV: 5000 IU/kg (five thousand IU/kg) as a single bolus dose

Hemodialysis/filtration >4 hours

• IV: Initial: 30-40 IU/kg, immediately, as a single dose

THEN

• IV: 10-15 IU/kg/hr as an infusion

Prevention of clotting in the extra-corporeal system during haemodialysis and haemofiltration
- Acute renal failure with high bleeding risk

• IV: Initial: 5-10 IU/kg, immediately, as a single dose

THEN

• IV: 4-5 IU/kg/hr as an infusion

Thromboprophylaxis
Moderate risk of thrombosis (abdominal and gynaecological surgery)

• SC: Initial: 2500 IU (two thousand five hundred) 1-2 hours pre-operatively; Then 2500 IU (two thousand five hundred), dly; Treatment duration: 5-7 days or until patient mobilised  

High risk of thrombosis (orthopaedic surgery or underlying malignancy)

• SC: Initial: 5000 IU (five thousand) the evening before surgery; Then 5000 IU (five thousand) dly, in the evening; Treatment duration: 5-7 days or until patient mobilised  

OR

• SC: 2500 IU (two thousand five hundred) 1-2 hours pre-operatively; 2500 IU (two thousand five hundred) 8-12hrs later; Then 5000 IU (five thousand), dly; Treatment duration: 5-7 days or until patient mobilised

Prolonged thromboprophylaxis in hip replacement surgery

• SC: Initial: 5000 IU (five thousand) the evening before operation; Then 5000 IU (five thousand), dly, in the evening; Treatment duration: 5 weeks

OR

• SC: 2500 IU (two thousand five hundred) 1-2 hours pre-operatively; 2500 IU (two thousand five hundred) 8-12hrs later; Then 5000 IU (five thousand), dly; Treatment duration: 5 weeks

Symptomatic treatment of venous thromboembolism in cancer patients

• SC: 100 IU/kg, 12hrly or 200 IU/kg, dly, for 30 days; Then 150 IU/kg, dly; Treatment duration: 6 months

Unstable angina
Non-Q wave myocardial infarction

Not for revascularisation therapy

• SC: 120 IU/kg, 12hrly; Max 20 000 IU (twenty thousand)/24hrs; Treatment duration: at least 6 days

Patients awaiting revascularisation therapy (Women <80kg; Men<70kg)

• SC: 120 IU/kg, 12hrly; Treatment duration: 5-7 days; Then 5000 IU (five thousand), 12hrly; Treatment duration: until procedure; Max treatment duration: 45 days

Patients awaiting revascularisation therapy (Women >80kg; Men>70kg)

• SC: 120 IU/kg, 12hrly; Treatment duration: 5-7 days; Then 7500 IU (seven thousand five hundred), 12hrly; Treatment duration: until procedure; Max treatment duration: 45 days

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Administer with aspirin therapy

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For obese patients, use actual body weight to calculate dose

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Do not administer IM

IM injection of other medical preparations should be avoided when dose exceeds 5 000 IU (five thousand)/24hrs due to the risk of haematoma formation

Not established for use in children

Pregnancy

• Safe; no evidence of risk in studies
• Dalteparin 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. Dalteparin 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. Epidural anaesthesia during childbirth is absolutely contraindicated in women who are being treated with high-dose anticoagulants. Caution is recommended when treating patients with an increased risk of haemorrhage, such as perinatal women. In pregnant women during the last trimester, dalteparin anti-Xa half-lives of 4 to 5 hours were measured
• Dalteparin formulations containing benzyl alcohol as a preservative should be avoided during pregnancy, as benzyl alcohol may cross the placenta
• 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 valve

Breastfeeding

• Caution; not recommended
• 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 the 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 breastfeeding child cannot be excluded. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with dalteparin should be made taking into account the benefit of breastfeeding to the child and the benefit of dalteparin therapy to the woman

Fertility

• Based 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

Renal Impairment

• CrCl ≥30ml/min: No dose adjustment recommended
• CrCl <30ml/min: Caution; dose adjustment recommended
  Adjustment should be based on anti-Factor Xa activity; Anti-Factor Xa measurement should be repeated after 3-4 new doses; Repeat until the desired anti-Factor Xa level is achieved

Hepatic Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Monitor closely; Repeated dosing may lead to accumulation increasing the risk for bleeding

Elderly

• No dose adjustment recommended

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Intracranial bleeds
• Spinal or epidural hematoma

Cardiovascular Disorders

• Prosthetic cardiac valve thrombosis
• Haemorrhage

Gastrointestinal Disorders

• Retroperitoneal bleeds

Hepatobiliary Disorders

• Transient elevation of transaminases

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Pruritus
• Skin necrosis
• Transient alopecia
• Rash
• Subcutaneous haematoma at injection site
• Pain at injection site

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylaxis
• Mild thrombocytopenia
• Heparin-induced thrombocytopenia

• Anticoagulant agents
• Platelet inhibitors
• Antihistamines
• Cardiac glycosides
• Tetracycline
• Ascorbic acid
• Intravenous nitroglycerine
• Penicillin
• Quinine
• Tobacco
• Agents that increase serum potassium

• Full blood count

Specific cases may require

• Anti-Xa levels
• Serum potassium

Pharmacokinetic (PK) properties: Bioavailability

• The bioavailability following s.c. injection is approximately 87% and the pharmacokinetics are not dose dependent
• The half life is prolonged in uraemic patients as dalteparin sodium is eliminated primarily through the kidneys

Dalteparin sodium is a low molecular weight heparin fraction. It activates the enzyme inhibitor antithrombin III by binding to it, thus potentiating its effect. This in turn inhibits the formation of factor Xa and thrombin, which has an antithrombotic effect.

Injection (per 0.2ml) 2500iu

• Fragmin pre-filled syringe (Pfizer) originator - Discontinued (20/12/19)

Injection (per 0.2ml) 5000iu

• Fragmin pre-filled syringe (Pfizer) originator - Discontinued (20/12/19)

Injection (per 0.5ml) 12 500iu

• Fragmin pre-filled syringe (Pfizer) originator - Discontinued (20/12/19)

Injection (per 0.6ml) 15 000iu

• Fragmin pre-filled syringe (Pfizer) originator - Discontinued (20/12/19)

Injection (per 0.72ml) 18 000iu

• Fragmin pre-filled syringe (Pfizer) originator - Discontinued (20/12/19)