9 QH Tel: 0845 610 1112

GP practices can obtain supplies through their Local Area Team stores. NHS Trusts can order supplies from www.nhsforms.co.ukor by emailing nhsforms@mmm.com.

InScotland, treatment booklets and starter information packs can be obtained by emailing stockorders.

dppas@theapsgroup.com or by fax on (0131⁾6299 967 Electronic copies of the booklets and further advice are also available atwww.npsa.nhs.uk/nrls/alerts-and-directives/

alerts/anticoagulant.

eiii^F88 i

Warfarin sodium

lINDICATIONS AND DOSE

Treatment and prophylaxis of thrombotic episodes (induction)

▶BY MOUTH

▶Neonate (initiated under specialist supervision):Initially 200micrograms/kg for1dose on day1, then reduced to 100micrograms/kg once daily for the following3^days, subsequent doses dependent on INR levels, induction dose may need to be altered according to condition (e.g.

abnormal liver function tests, cardiac failure), concomitant interacting drugs, and if baseline INR above1^.3^.

▶Child:Initially200micrograms/kg (max. per dose 10^{mg) for}1dose on day1, then reduced to 100micrograms/kg once daily (max. per dose5^{mg) for} the following3days, subsequent doses adjusted according to INR levels, induction dose may need to be altered according to condition (e.g. abnormal liver function tests, cardiac failure), concomitant interacting drugs, and if baseline INR above1^.3

Treatment and prophylaxis of thrombotic episodes following induction dose (if INR still below1^.4⁾

▶BY MOUTH

▶Neonate:200micrograms/kg once daily.

▶Child:200micrograms/kg once daily (max. per dose 10^mg)

Treatment and prophylaxis of thrombotic episodes following induction dose (if INR above3^.0⁾

▶BY MOUTH

▶Neonate:50micrograms/kg once daily.

▶Child:50micrograms/kg once daily (max. per dose 2^.5^mg)

Treatment and prophylaxis of thrombotic episodes following induction dose (if INR above3^.5⁾

▶BY MOUTH

▶Neonate:Dose to be omitted.

▶Child:Dose to be omitted

Treatment and prophylaxis of thrombotic episodes (usual maintenance)

▶BY MOUTH

▶Neonate:Maintenance100–300micrograms/kg once daily, doses up to400micrograms/kg once daily may be required especially if bottle fed, to be adjusted according to INR.

▶Child:Maintenance100–300micrograms/kg once daily, doses up to400micrograms/kg once daily may be required especially if bottle fed, to be adjusted according to INR

lUNLICENSED USENot licensed for use in children.

lPREGNANCYBabies of mothers taking warfarin at the time of delivery need to be offered immediate prophylaxis with intramuscular phytomenadione (vitamin K₁).

lBREAST FEEDINGNot present in milk in significant amounts and appears safe. Risk of haemorrhage which is increased by vitamin K deficiency.

lHEPATIC IMPAIRMENTAvoid in severe impairment, especially if prothrombin time is already prolonged.

lRENAL IMPAIRMENTUse with caution in mild to moderate impairment. In severe renal impairment, monitor INR more frequently.

lPRESCRIBING AND DISPENSING INFORMATION Dietary differencesInfant formula is supplemented with vitamin K, which makes formula-fed infants resistant to warfarin; they may therefore need higher doses. In contrast breast milk contains low concentrations of vitamin K making breast-fed infants more sensitive to warfarin.

lPATIENT AND CARER ADVICEAnticoagulant card to be provided.

Medicines for Children leaflet: Warfarin for the treatment and prevention of thrombosiswww.medicinesforchildren.org.uk/

warfarin-treatment-and-prevention-thrombosis lMEDICINAL FORMS

There can be variation in the licensing of different medicines containing the same drug. Forms available from special-order manufacturers include: capsule, oral suspension, oral solution Tablet

CAUTIONARY AND ADVISORY LABELS10

▶Warfarin sodium (Non-proprietary)

Warfarin sodium 500 microgramWarfarin500microgram tablets| 28tablet^P£1.92DT price = £1.54

Warfarin sodium 1 mgWarfarin1mg tablets|28tablet^P £1.16 DT price = £0.76|500tablet^P£14.82

Warfarin sodium 3 mgWarfarin3mg tablets|28tablet^P£1.20 DT price = £0.79|500tablet^P£15.71

Warfarin sodium 4 mgCoumadin4mg tablets|100tablet^Pno price available

Warfarin sodium 5 mgWarfarin5mg tablets|28tablet^P£1.29 DT price = £0.82|500tablet^Pno price available

▶Marevan(AMCo)

Warfarin sodium 1 mgMarevan1mg tablets|28tablet^P £0.31 DT price = £0.76

Warfarin sodium 3 mgMarevan3mg tablets|28tablet^P £0.35 DT price = £0.79

Warfarin sodium 5 mgMarevan5mg tablets|28tablet^P £0.47 DT price = £0.82

Oral suspension

CAUTIONARY AND ADVISORY LABELS10

▶Warfarin sodium (Non-proprietary)

Warfarin sodium 1 mg per 1 mlWarfarin1mg/ml oral suspension sugar free sugar-free|150ml^P £108.00DT price = £108.00

BNFC2016–2017

Thromboembolism 89

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4 Blood pressure conditions 4.1 Hypertension

Hypertension

Overview

Hypertension in children and adolescents can have a substantial effect on long-term health. Possible causes of hypertension (e.g. congenital heart disease, renal disease and endocrine disorders) and the presence of any complications (e.g. left ventricular hypertrophy) should be established. Treatment should take account of contributory factors and any factors that increase the risk of

cardiovascular complications.

Serious hypertension is rare inneonatesbut it can present with signs of congestive heart failure; the cause is often renal and can follow embolic arterial damage.

Children (or their parents or carers) should be given advice on lifestyle changes to reduce blood pressure or

cardiovascular risk; these include weight reduction (in obese children), reduction of dietary salt, reduction of total and saturated fat, increasing exercise, increasing fruit and vegetable intake, and not smoking.

Indications for antihypertensive therapy in children include symptomatic hypertension, secondary hypertension, hypertensive target-organ damage, diabetes mellitus, persistent hypertension despite lifestyle measures, and pulmonary hypertension. The effect of antihypertensive treatment on growth and development is not known;

treatment should be started only if benefits are clear.

Antihypertensive therapy should be initiated with a single drug at the lowest recommended dose; the dose can be increased until the target blood pressure is achieved. Once the highest recommended dose is reached, or sooner if the patient begins to experience side-effects, a second drug may be added if blood pressure is not controlled. If more than one drug is required, these should be given as separate products to allow dose adjustment of individual drugs, butfixed-dose combination products may be useful in adolescents if compliance is a problem.

Acceptable drug classes for use in children with hypertension includeACE inhibitors,alpha-blockers, beta-blockers,calcium-channel blockers, andthiazide diuretics. There is limited information on the use of angiotensin-II receptor antagonistsin children. Diuretics and beta-blockers have a long history of safety and efficacy in children. The newer classes of antihypertensive drugs, including ACE inhibitors and calcium-channel blockers have been shown to be safe and effective in short-term studies in children. Refractory hypertension may require additional treatment with agents such as minoxidil p.108or clonidine hydrochloride p.93^.

Other measures to reduce cardiovascular risk Aspirin p.83may be used to reduce the risk of cardiovascular events; however, concerns about an increased risk of bleeding and Reye’s syndrome need to be considered.

Astatincan be of benefit in older children who have a high risk of cardiovascular disease and have

hypercholesterolaemia.

Hypertension in diabetes

Hypertension can occur in type2diabetes and treatment prevents both macrovascular and microvascular

complications. ACE inhibitors may be considered in children with diabetes and microalbuminaemia or proteinuric renal disease. Beta-blockers are best avoided in children with, or at a high risk of developing, diabetes, especially when combined with a thiazide diuretic.

Hypertension in renal disease

ACE inhibitors may be considered in children with micro-albuminuria or proteinuric renal disease. High doses of loop diuretics may be required. Specific cautions apply to the use of ACE inhibitors in renal impairment, but ACE inhibitors may be effective. Dihydropyridine calcium-channel blockers may be added.

Hypertension in pregnancy

High blood pressure in pregnancy may usually be due to pre-existing essential hypertension or to pre-eclampsia.

Methyldopa is safe in pregnancy. Beta-blockers are effective and safe in the third trimester. Modified-release

preparations of nifedipine p.100[unlicensed] are also used for hypertension in pregnancy. Intravenous administration of labetalol hydrochloride p.95can be used to control hypertensive crises; alternatively hydralazine hydrochloride p.108can be given by the intravenous route.

Hypertensive emergencies

Hypertensive emergencies in children may be accompanied by signs of hypertensive encephalopathy, including seizures.

Controlled reduction in blood pressure over72–96^{hours is} essential; rapid reduction can reduce perfusion leading to organ damage. Treatment should be initiated with intravenous drugs; once blood pressure is controlled, oral therapy can be started. It may be necessary to infusefluids particularly during thefirst12hours to expand plasma volume should the blood pressure drop too rapidly.

Controlled reduction of blood pressure is achieved by intravenous administration of labetalol hydrochloride or sodium nitroprusside p.109. Esmolol hydrochloride p.98^is useful for short-term use and has a short duration of action.

Nicardipine hydrochloride p.100can be administered as a continuous intravenous infusion for life-threatening hypertension in paediatric intensive care settings. In less severe cases, nifedipine capsules can be used.

Other antihypertensive drugs which can be given intravenously include hydralazine hydrochloride and clonidine hydrochloride.

Hypertension in acute nephritis occurs as a result of sodium and water retention; it should be treated with sodium andfluid restriction, and with furosemide p.132^; antihypertensive drugs may be added if necessary.

Also see advice on short-term management of hypertensive episodes in phaeochromocytoma.

Phaeochromocytoma

Long-term management of phaeochromocytoma involves surgery. However, surgery should not take place until there is adequate blockade of both alpha- and beta-adrenoceptors.

Alpha-blockers are used in the short-term management of hypertensive episodes in phaeochromocytoma. Once alpha blockade is established, tachycardia can be controlled by the cautious addition of a blocker; a cardioselective beta-blocker is preferred. There is no nationwide consensus on the optimal drug regimen or doses used for the management of phaeochromocytoma.

Phenoxybenzamine hydrochloride p.109, a powerful alpha-blocker, is effective in the management of phaeochromocytoma but it has many side-effects.

Pulmonary hypertension

Only pulmonaryarterialhypertension is currently suitable for drug treatment. Pulmonary arterial hypertension includes persistent pulmonary hypertension of the newborn, idiopathic pulmonary arterial hypertension in children, and pulmonary hypertension related to congenital heart disease and cardiac surgery.

Some types of pulmonary hypertension are treated with vasodilator antihypertensive therapy and oxygen. Diuretics may also have a role in children with right-sided heart failure.

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Initial treatment ofpersistent pulmonary hypertension of the newborninvolves the administration ofnitric oxide;

epoprostenol p.110can be used until nitric oxide is available. Oral sildenafil p.111may be helpful in less severe cases. Epoprostenol and sildenafil can cause profound systemic hypotension. In rare circumstances either tolazoline p.112or magnesium sulfate p.556can be given by intravenous infusion when nitric oxide and epoprostenol have failed.

Treatment ofidiopathic pulmonary arterial hypertensionis determined by acute vasodilator testing; drugs used for treatment include calcium-channel blockers

(usuallynifedipine), long-term intravenous epoprostenol, nebulised iloprost p.110, bosentan p.111, or sildenafil.

Anticoagulation (usually with warfarin sodium p.89^{) may} also be required to prevent secondary thrombosis.

Inhaled nitric oxideis a potent and selective pulmonary vasodilator. It acts on cyclic guanosine monophosphate (cGMP) resulting in smooth muscle relaxation. Inhaled nitric oxide is used in the treatment of persistent pulmonary hypertension of the newborn, and may also be useful in other forms of arterial pulmonary hypertension. Dependency can occur with high doses and prolonged use; to avoid rebound pulmonary hypertension the drug should be withdrawn gradually, often with the aid of sildenafil p.111^.

Excess nitric oxide can cause methaemoglobinaemia;

therefore, methaemoglobin concentration should be measured regularly, particularly in neonates.

Nitric oxide increases the risk of haemorrhage by inhibiting platelet aggregation, but it does not usually cause bleeding.

Epoprostenol (prostacyclin) p.110is a prostaglandin and a potent vasodilator. It is used in the treatment of persistent pulmonary hypertension of the newborn, idiopathic pulmonary arterial hypertension, and in the acute phase following cardiac surgery. It is given by continuous24^-hour intravenous infusion.

Epoprostenol is a powerful inhibitor of platelet aggregation and there is a possible risk of haemorrhage. It is sometimes used as an antiplatelet in renal dialysis when heparins are unsuitable or contra-indicated. It can also cause serious systemic hypotension and, if withdrawn suddenly, can cause pulmonary hypertensive crisis.

Children on prolonged treatment can become tolerant to epoprostenol, and therefore require an increase in dose.

Iloprost p.110is a synthetic analogue of epoprostenol and is efficacious when nebulised in adults with pulmonary arterial hypertension, but experience in children is limited. It is more stable than epoprostenol and has a longer half-life.

Bosentan p.111is a dual endothelin receptor antagonist used orally in the treatment of pulmonary arterial hypertension. The concentration of endothelin, a potent vasoconstrictor, is raised in sustained pulmonary hypertension.

Sildenafil, a vasodilator developed for the treatment of erectile dysfunction, is also used for pulmonary arterial hypertension. It is used either alone or as an adjunct to other drugs.

Sildenafil is a selective phosphodiesterase type-5^inhibitor.

Inhibition of this enzyme in the lungs enhances the vasodilatory effects of nitric oxide and promotes relaxation of vascular smooth muscle.

Sildenafil has also been used in pulmonary hypertension for weaning children off inhaled nitric oxide following cardiac surgery, and less successfully in idiopathic pulmonary arterial hypertension.

Tolazoline p.112is now rarely used to correct pulmonary artery vasospasm in pulmonary hypertension of the newborn as better alternatives are available. Tolazoline is an alpha-blocker and produces both pulmonary and systemic vasodilation.

Antihypertensive drugs

Vasodilator antihypertensive drugs

Vasodilators have a potent hypotensive effect, especially when used in combination with a beta-blocker and a thiazide.Important:see Hypertension (hypertensive emergencies) for a warning on the hazards of a very rapid fall in blood pressure.

Hydralazine hydrochloride p.108is given by mouth as an adjunct to other antihypertensives for the treatment of resistant hypertension but is rarely used; when used alone it causes tachycardia andfluid retention.

Sodium nitroprusside p.109is given by intravenous infusion to control severe hypertensive crisis when parenteral treatment is necessary. At low doses it reduces systemic vascular resistance and increases cardiac output; at high doses it can produce profound systemic hypotension— continuous blood pressure monitoring is therefore essential.

Sodium nitroprusside may also be used to control paradoxical hypertension after surgery for coarctation of the aorta.

Minoxidil p.108should be reserved for the treatment of severe hypertension resistant to other drugs. Vasodilatation is accompanied by increased cardiac output and tachycardia and children developfluid retention. For this reason the addition of a beta-blocker and a diuretic (usually furosemide p.132, in high dosage) are mandatory. Hypertrichosis is troublesome and renders this drug unsuitable for females.

Prazosin p.92and doxazosin p.458have alpha-blocking and vasodilator properties.

Centrally acting antihypertensive drugs

Methyldopa, a centrally acting antihypertensive, is of little value in the management of refractory sustained hypertension in infants and children. On prolonged use it is associated withfluid retention (which may be alleviated by concomitant use of diuretics).

Methyldopa is also effective for the management of hypertension in pregnancy.

Clonidine hydrochloride p.93is also a centrally acting antihypertensive but has the disadvantage that sudden withdrawal may cause a hypertensive crisis. Clonidine hydrochloride is also used under specialist supervision for pain management, sedation, and opioid withdrawal, attention deficit hyperactivity disorder, and Tourette syndrome.

Adrenergic neurone blocking drugs

Adrenergic neurone blocking drugs prevent the release of noradrenaline from postganglionic adrenergic neurones.

These drugs do not control supine blood pressure and may cause postural hypotension. For this reason they have largely fallen from use in adults and are rarely used in children.

Alpha-adrenoceptor blocking drugs

Doxazosin and prazosin have post-synaptic alpha-blocking and vasodilator properties and rarely cause tachycardia.

They can, however, reduce blood pressure rapidly after the first dose and should be introduced with caution.

Alpha-blockers can be used with other antihypertensive drugs in the treatment of resistant hypertension.

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Drugs affecting the renin-angiotensin system

Angiotensin-converting enzyme inhibitors Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit the conversion of angiotensin I to angiotensin II. The main indications of ACE inhibitors in children are shown below. In infants and young children, captopril p.103^is often consideredfirst.

Initiation under specialist supervision

Treatment with ACE inhibitors should be initiated under specialist supervision and with careful clinical monitoring in children.

Heart failure

ACE inhibitors have a valuable role in all grades of heart failure, usually combined with a loop diuretic. Potassium supplements and potassium-sparing diuretics should be discontinued before introducing an ACE inhibitor because of the risk of hyperkalaemia. Profoundfirst-dose hypotension can occur when ACE inhibitors are introduced to children with heart failure who are already taking a high dose of a loop diuretic. Temporary withdrawal of the loop diuretic reduces the risk, but can cause severe rebound pulmonary oedema.

Hypertension

ACE inhibitors may be considered for hypertension when thiazides and beta-blockers are contra-indicated, not tolerated, or fail to control blood pressure; they may be considered for hypertension in children with type1^diabetes with nephropathy. ACE inhibitors can reduce blood pressure very rapidly in some patients particularly in those receiving diuretic therapy.

Diabetic nephropathy

ACE inhibitors also have a role in the management of diabetic nephropathy.

Renal effects

Renal function and electrolytes should be checked before starting ACE inhibitors (or increasing the dose) and monitored during treatment (more frequently if features mentioned below are present). Hyperkalaemia and other side-effects of ACE inhibitors are more common in children with impaired renal function and the dose may need to be reduced.

Concomitant treatment with NSAIDs increases the risk of renal damage, and potassium-sparing diuretics (or potassium-containing salt substitutes) increase the risk of hyperkalaemia.

In children with severe bilateral renal artery stenosis (or severe stenosis of the artery supplying a single functioning kidney), ACE inhibitors reduce or abolish glomerular filtration and are likely to cause severe and progressive renal failure. They are therefore contra-indicated in children known to have these forms of critical renovascular disease.

ACE inhibitor treatment is unlikely to have an adverse effect on overall renal function in children with severe unilateral renal artery stenosis and a normal contralateral kidney, but glomerularfiltration is likely to be reduced (or even abolished) in the affected kidney and the long-term consequences are unknown.

ACE inhibitors are therefore best avoided in those with known or suspected renovascular disease, unless the blood pressure cannot be controlled by other drugs. If they are used in these circumstances renal function needs to be monitored.

ACE inhibitors should also be used with particular caution in children who may have undiagnosed and clinically silent renovascular disease. ACE inhibitors are useful for the management of hypertension and proteinuria in children with nephritis. They are thought to have a beneficial effect

by reducing intra-glomerular hypertension and protecting the glomerular capillaries and membrane.

ACE inhibitors in combination with other drugs Concomitant diuretics

ACE inhibitors can cause a very rapid fall in blood pressure in volume-depleted children; treatment should therefore be initiated with very low doses. In some children the diuretic dose may need to be reduced or the diuretic discontinued at least24hours beforehand (may not be possible in heart failure—risk of pulmonary oedema). If high-dose diuretic therapy cannot be stopped, close observation is recommended after administration of thefirst dose of ACE inhibitor, for at least2hours or until the blood pressure has stabilised.

Angiotensin-II receptor antagonists

Candesartan cilexetil p.106, losartan potassium p.107^and valsartan p.107^{are speci}fic angiotensin-II receptor antagonists with many properties similar to those of the ACE inhibitors. However, unlike ACE inhibitors, they do not inhibit the breakdown of bradykinin and other kinins, and thus are less likely to cause the persistent dry cough which can complicate ACE inhibitor therapy. They are therefore a useful alternative for children who have to discontinue an ACE inhibitor because of persistent cough.

Candesartan cilexetil, losartan potassium or valsartan can be used as an alternative to an ACE inhibitor in the management of hypertension.

Renal effects

Angiotensin-II receptor antagonists should be used with caution in renal artery stenosis (see also Renal effects under ACE Inhibitors, above).

Neonates

The neonatal response to treatment with ACE inhibitors is very variable, and some neonates develop profound hypotension with even small doses; a test-dose should be used initially and increased cautiously. Adverse effects such as apnoea, seizures, renal failure, and severe unpredictable hypotension are very common in thefirst month of life and it is therefore recommended that ACE inhibitors are avoided whenever possible, particularly in preterm neonates.

Drugs used for Hypertension not listed below Chlortalidone, p.134

.

Diazoxide p.434

ALPHA-ADRENOCEPTOR BLOCKERS

Prazosin

lINDICATIONS AND DOSE Hypertension

▶BY MOUTH

▶Child 1 month–11 years:Initially10–15micrograms/kg 2–4times a day, initial dose to be taken at bedtime, then increased to500micrograms/kg daily in divided doses, dose to be increased gradually; maximum20^mg per day

▶Child 12–17 years:Initially500^micrograms2–3^{times a} day for3^-7days, initial dose to be taken at bedtime, then increased to1^mg2–3times a day for a further 3–7days, then increased if necessary up to20^{mg daily} in divided doses, dose should be increased gradually

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