2 Cardiovascular system
2.8 Anticoagulants and protamine
2.8.1 Parenteral anticoagulants
HEPARIN
Cautions see notes above; concomitant use of drugs that increase risk of bleeding;interactions:
Appendix 1 (heparin)
Heparin-induced thrombocytopeniaClinically important heparin-induced thrombocytopenia is immune-mediated and does not usually develop until after 5–10 days; it can be complicated by thrombosis. Platelet counts should be measured just before treatment with heparin or low molecular weight heparins, and regular monitoring of platelet counts is recommended if given for longer than 4 days. Signs of heparin-induced thrombocytopenia include a 50% reduction of platelet count, thrombosis, or skin allergy. If heparin-induced thrombocytopenia is strongly suspected or confirmed, heparin should bestopped and an alternative anticoagulant, such as danaparoid, should be given. Ensure platelet counts return to normal range in those who require warfarin
HyperkalaemiaInhibition of aldosterone secretion by heparin (including low molecular weight heparins) can result in hyperkalaemia; patients with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium, or those taking potassium-sparing drugs seem to be more susceptible. The risk appears to increase with duration of therapy and the CSM has recommended that plasma-potassium concentration should be measured in children at risk of hyperkalaemia before starting heparin and monitored regularly thereafter, particularly if heparin is to be continued for longer than 7 days
Hepatic impairment risk of bleeding increased—
possibly reduce dose in severe impairment Renal impairment risk of bleeding increased in severe impairment—dose may need to be reduced Pregnancy does not cross the placenta; maternal osteoporosis reported after prolonged use; multi-dose vials may contain benzyl alcohol—some manufacturers advise avoid
Breast-feeding not excreted in milk due to high molecular weight
Contra-indications haemophilia and other hae-morrhagic disorders, thrombocytopenia (includ-ing history of heparin-induced thrombocytope-nia), recent cerebral haemorrhage, severe hypertension; severe liver disease (including oesophageal varices), peptic ulcer; after major trauma or recent surgery to eye or nervous sys-tem; acute bacterial endocarditis; spinal or epi-dural anaesthesia with treatment doses of hep-arin; hypersensitivity to heparin or low molecular weight heparins
Side-effects haemorrhage (see notes above), thrombocytopenia (see Cautions), rarely rebound hyperlipidaemia following heparin withdrawal, priapism, hyperkalaemia (see Cautions), osteo-porosis (risk lower with low molecular weight heparins), alopecia on prolonged use, injection-site reactions, skin necrosis, and hypersensitivity reactions (including urticaria, angioedema, and anaphylaxis)
Licensed use Some preparations licensed for use in children
Indication and dose
Maintenance of neonatal umbilical arterial catheter
. By intravenous infusion Neonate0.5 units/hour
Treatment of thrombotic episodes . By intravenous administration
Neonateinitially 75 units/kg (50 units/kg if under 35 weeks post-menstrual age) by intra-venous injection, then by continuous intraintra-venous infusion 25 units/kg/hour, adjusted according to APTT
Child 1 month–1 yearinitially 75 units/kg by intravenous injection, then by continuous intra-venous infusion 25 units/kg/hour, adjusted according to APTT
Child 1–18 yearsinitially 75 units/kg by intra-venous injection, then by continuous intraintra-venous infusion 20 units/kg/hour, adjusted according to APTT
. By subcutaneous injection
Child 1 month–18 years250 units/kg twice daily, adjusted according to APTT Prophylaxis of thrombotic episodes . By subcutaneous injection
Child 1 month–18 years100 units/kg (max.
5000 units) twice daily, adjusted according to APTT
Prevention of clotting in extracorporeal circuits consult product literature
Administration for continuous intravenous infusion, dilute with Glucose 5% or Sodium Chloride 0.9%.
Maintenance of neonatal umbilical arterial catheter, dilute 50 units to a final volume of 50 mL with Sodium Chloride 0.45% or use ready-made bag containing 500 units in 500 mL Sodium Chloride 0.9%; infuse at 0.5 mL/hour
Neonatal intensive care (treatment of thrombosis), dilute 1250 units/kg body-weight to a final volume of 50 mL with infusion fluid; an intra-venous infusion rate of 1 mL/hour provides a dose of 25 units/kg/hour
Heparin Sodium(Non-proprietary)A
Injection, heparin sodium 1000 units/mL, net price 1-mL amp = 37p, 5-mL amp = 93p, 5-mL vial = 92p, 10-mL amp = £1.60, 20-mL amp = £2.63;
5000 units/mL, 1-mL amp = 72p, 5-mL amp =
£1.87, 5-mL vial = £2.09; 25 000 units/mL, 0.2-mL amp = 92p, 1-mL amp = £1.90, 5-mL vial = £3.68 Excipientsmay include benzyl alcohol (avoid in neonates, see Excipients, p. 3)
Heparin Calcium(Non-proprietary)A
Injection, heparin calcium 25 000 units/mL, net price 0.2-mL amp = 73p
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Low molecular weight heparins
Dalteparin, enoxaparin, and tinzaparin are low molecular weight heparins used for treatment and prophylaxis of thrombotic episodes in children. Their duration of action is longer than that of unfractionated heparin and in adults and older children once-daily subcutaneous dosage is sometimes possible; however, younger children require relatively higher doses (possibly due to larger volume of dis-tribution, altered heparin pharmacokinetics, or lower plasma concentrations of antithrombin) and twice daily dosage is sometimes necessary. Low molecular weight heparins are convenient to use, especially in children with poor venous access. Routine monitoring of anti-Factor Xa activity is not usually required except in neonates; monitoring may also be necessary in severely ill children and those with renal or hepatic impairment.
Haemorrhage See under Heparin.
Hepatic impairment Reduce dose in severe hepatic impairment—risk of bleed-ing may be increased.
Renal impairment See under individual drug.
Pregnancy Not known to be harmful, low molecular weight heparins do not cross the placenta.
Breast-feeding Due to the relatively high molecular weight of these drugs and inactivation in the gastro-intestinal tract, passage into breast-milk and absorption by the nursing infant are likely to be negligible; however manufacturers advise avoid.
DALTEPARIN SODIUM
Cautions see under Heparin and notes above Hepatic impairment see notes above Renal impairment risk of bleeding may be increased—dose reduction and monitoring of anti-factor Xa may be required; use of unfractionated heparin may be preferable
Pregnancy see notes above Breast-feeding see notes above Contra-indications see under Heparin Side-effects see under Heparin
Licensed use not licensed for use in children Indication and dose
Treatment of thrombotic episodes . By subcutaneous injection
Neonate100 units/kg twice daily Child 1 month–12 years100 units/kg twice daily
Child 12–18 years200 units/kg (max.
18 000 units) once daily, if increased risk of bleeding reduced to 100 units/kg twice daily Treatment of venous thromboembolism in pregnancy
. By subcutaneous injection
Child 12–18 yearsearly pregnancy body-weight under 50 kg, 5000 units twice daily;
body-weight 50–70 kg, 6000 units twice daily;
body-weight 70–90 kg, 8000 units twice daily;
body-weight over 90 kg, 10 000 units twice daily Prophylaxis of thrombotic episodes
. By subcutaneous injection Neonate100 units/kg once daily Child 1 month–12 years100 units/kg once daily
Child 12–18 years2500–5000 units once daily
Fragminc(Pharmacia)A
Injection(single-dose syringe), dalteparin sodium 12 500 units/mL, net price 2500-unit (0.2-mL) syringe = £1.86; 25 000 units/mL, 5000-unit (0.2-mL) syringe = £2.82, 7500-unit (0.3-(0.2-mL) syringe =
£4.23, 10 000-unit (0.4-mL) syringe = £5.65, 12 500-unit (0.5-mL) syringe = £7.06, 15 000-500-unit (0.6-mL) syringe = £8.47, 18 000-unit (0.72-mL) syringe =
£10.16
Injection, dalteparin sodium 2500 units/mL (for subcutaneous or intravenous use), net price 4-mL (10 000-unit) amp = £5.12; 10 000-units/mL (for subcutaneous or intravenous use), 1-mL (10 000-unit) amp = £5.12; 25 000 units/mL (for subcuta-neous use only), 4-mL (100 000-unit) vial = £48.66 Injection(graduated syringe), dalteparin sodium 10 000 units/mL, net price 1-mL (10 000-unit) syringe = £5.65
ENOXAPARIN SODIUM
Cautions see under Heparin and notes above Hepatic impairment see notes above
Renal impairment risk of bleeding may be increased; reduce dose if estimated glomerular fil-tration rate less than 30 mL/minute/1.73 m2;
mon-BNFC 2009 2.8.1 Parenteral anticoagulants
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2Cardiovascularsystem
itoring of anti-factor Xa may be required; use of unfractionated heparin may be preferable Pregnancy see notes above
Breast-feeding see notes above Contra-indications see under Heparin Side-effects see under Heparin
Licensed use not licensed for use in children Indication and dose
Treatment of thrombotic episodes . By subcutaneous injection
Neonate1.5–2 mg/kg twice daily Child 1–2 months1.5 mg/kg twice daily Child 2 months–18 years1 mg/kg twice daily Treatment of venous thromboembolism in pregnancy
. By subcutaneous injection
Child 12–18 yearsearly pregnancy body-weight under 50 kg, 40 mg (4000 units) twice daily; body-weight 50–70 kg, 60 mg (6000 units) twice daily; body-weight 70–90 kg, 80 mg (8000 units) twice daily; body-weight over 90 kg, 100 mg (10 000 units) twice daily
Prophylaxis of thrombotic episodes . By subcutaneous injection
Neonate750 micrograms/kg twice daily Child 1–2 months750 micrograms/kg twice daily
Child 2 months–18 years500 micrograms/kg twice daily; max. 40 mg daily
Clexanec(Rhoˆne-Poulenc Rorer)A
Injection, enoxaparin sodium 100 mg/mL, net price 20-mg (0.2-mL, 2000-units) syringe = £3.15, 40-mg (0.4-mL, 4000-units) syringe = £4.20, 60-mg (0.6-mL, 6000-units) syringe = £4.75, 80-mg (0.8-mL, 8000-units) syringe = £5.40, 100-mg (1-(0.8-mL, 10 000-units) syringe = £6.69, 300-mg (3-mL, 30 000-units) vial (ClexanecMulti-Dose) = £22.20;
150 mg/mL (ClexanecForte), 120-mg (0.8-mL, 12 000-units) syringe = £9.77, 150-mg (1-mL, 15 000-units) syringe = £11.10
TINZAPARIN SODIUM
Cautions see under Heparin and notes above Hepatic impairment see notes above Renal impairment risk of bleeding may be increased—dose reduction and monitoring of anti-factor Xa may be required; unfractionated heparin may be preferable
Pregnancy see notes above; also vials contain benzyl alcohol—manufacturer advises avoid Breast-feeding see notes above Contra-indications see under Heparin Side-effects see under Heparin
Licensed use not licensed for use in children Indication and dose
Treatment of thrombotic episodes . By subcutaneous injection
Child 1–2 months275 units/kg once daily Child 2 months–1 year250 units/kg once daily Child 1–5 years240 units/kg once daily Child 5–10 years200 units/kg once daily Child 10–18 years175 units/kg once daily
Treatment of venous thromboembolism in pregnancy
. By subcutaneous injection
Child 12–18 years175 units/kg once daily (based on early pregnancy body-weight) Prophylaxis of thrombotic episodes . By subcutaneous injection
Child 1 month–18 years50 units/kg once daily
Innohepc(LEO)A
Injection, tinzaparin sodium 10 000 units/mL, net price 2500-unit (0.25-mL) syringe = £1.98, 3500-unit (0.35-mL) syringe = £2.77, 4500-3500-unit (0.45-mL) syringe = £3.56, 20 000-unit (2-mL) vial = £10.56 Injection, tinzaparin sodium 20 000 units/mL, net price 0.5-mL (10 000-unit) syringe = £8.98, 0.7-mL (14 000-unit) syringe = £12.57, 0.9-mL (18 000-unit) syringe = £16.16, 2-mL (40 000-unit) vial = £34.20 Excipientsinclude benzyl alcohol (in vials) (avoid in neonates, see Excipients, p. 3), sulphites (in 20 000 units/mL vial and syringe)
Heparinoids
Danaparoid is a heparinoid that has a role in children who develop thrombocy-topenia in association with heparin, providing they have no evidence of cross-reactivity.
DANAPAROID SODIUM
Cautions recent bleeding or risk of bleeding;
concomitant use of drugs that increase risk of bleeding; antibodies to heparins (risk of antibody-induced thrombocytopenia)
Hepatic impairment use with caution in moder-ate impairment (increased risk of bleeding); avoid in severe impairment unless no alternative Renal impairment use with caution in moderate impairment; increased risk of bleeding (monitor ENOXAPARIN SODIUM (continued)
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anti-Factor Xa activity); avoid in severe impairment unless child has heparin-induced thrombocytope-nia and no alternative available
Pregnancy limited information available but not known to be harmful—manufacturer advises avoid Breast-feeding amount probably too small to be harmful but manufacturer advises avoid Contra-indications haemophilia and other
hae-morrhagic disorders, thrombocytopenia (unless patient has heparin-induced thrombocytopenia), recent cerebral haemorrhage, severe hyper-tension, active peptic ulcer (unless this is the reason for operation), diabetic retinopathy, acute bacterial endocarditis, spinal or epidural anaes-thesia with treatment doses of danaparoid Side-effects haemorrhage; hypersensitivity
reac-tions (including rash)
Licensed use not licensed for use in children Indication and dose
Thromboembolic disease in children with his-tory of heparin-induced thrombocytopenia . By intravenous administration
Neonateinitially 30 units/kg by intravenous injection then by continuous intravenous infusion 1.2–2 units/kg/hour adjusted according to coa-gulation activity
Child 1 month–16 yearsinitially 30 units/kg (max. 1250 units if bodyweight under 55 kg, 2500 units if over 55 kg) by intravenous injection then by continuous intravenous infusion 1.2–
2 units/kg/hour adjusted according to coagula-tion activity
Child 16–18 yearsinitially 2500 units (1250 units if bodyweight under 55 kg, 3750 units if over 90 kg) by intravenous injection then by continuous intravenous infusion 400 units/
hour for 2 hours, then 300 units/hour for 2 hours, then 200 units/hour for 5 days adjusted accord-ing to coagulation activity
Administration for intravenous infusion, dilute with Glucose 5% or Sodium Chloride 0.9%
Orgaranc(Organon)A
Injection, danaparoid sodium 1250 units/mL, net price 0.6-mL amp (750 units) = £29.80
Heparin flushes
The use of heparin flushes should be kept to a minimum. For maintaining patency of peripheral venous catheters, sodium chloride 0.9% injection is as effective as heparin flushes. The role of heparin flushes in maintaining patency of arterial and central venous catheters is unclear.
Heparin Sodium(Non-proprietary)A
Solution, heparin sodium 10 units/mL, net price 5-mL amp = 25p; 100 units/5-mL, 2-5-mL amp = 28p Excipientsmay include benzyl alcohol (avoid in neonates, see Excipients, p. 3)
Epoprostenol
Epoprostenol (prostacyclin) can be given to inhibit platelet aggregation during renal dialysis either alone or with heparin. For its use in pulmonary hypertension, see section 2.5.1.2. It is a potent vasodilator and therefore its side-effects include flushing, headache, and hypotension.