2 Cardiovascular system
2.12 Lipid-regulating drugs
Atherosclerosis begins in childhood and raised serum-cholesterol in children is associated with cardiovascular disease in adulthood. Lowering the cholesterol, without hindering growth and development in children and adolescents, should reduce the risk of cardiovascular disease in later life.
The risk factors for developing cardiovascular disease include raised serum cholesterol concentration, smoking, hypertension, impaired glucose tolerance, male sex, ethnicity, obesity, triglyceride concentration, chronic kidney disease, and a family history of cardiovascular disease. In children with heterozygous familial hypercholesterolaemia, the family history of cardiovascular disease is most important when considering initiation of a lipid-regulating drug. Homozy-gous familial hypercholesterolaemia is rare and requires specialist management.
Secondary causes of hypercholesterolaemia should be addressed, these include diet, diabetes mellitus, hypothyroidism (see below), nephrotic syndrome, obstruc-tive biliary disease, glycogen storage disease, and drugs such as corticosteroids.
Treatment Dietary intervention is the mainstay of treatment of hyper-cholesterolaemia in children. The aim is to reduce the risk of atherosclerosis whilst ensuring adequate growth and development. Advice should also be given on lifestyle measures (e.g. increased exercise, and if appropriate, stopping smoking). Blood pressure should also be reduced if required (section 2.5).
When 6–12 months of dietary intervention alone has failed, drug therapy is indicated in children 10 years and over (rarely necessary in younger children) who are at a high risk of developing cardiovascular disease. Dietary therapy and lifestyle measures should continue even if lipid-regulating drugs have been introduced.
Lipid-regulating drugs are considered if dietary intervention fails to reduce total serum-cholesterol adequately; experience of their use in children is limited and they should be initiated on specialist advice.
Statins (atorvastatin, pravastatin, and simvastatin) are generally well tolerated;
atorvastatin and simvastatin are considered to be the drugs of first choice.Bile acid sequestrants are also available but tolerability of and compliance with these drugs is poor, and their use is declining.
Evidence for the use of afibrate (bezafibrate or fenofibrate) in children is limited;
fibrates should be considered only if dietary intervention and treatment with a statin and a bile acid sequestrant is unsuccessful or contra-indicated.
In hypertriglyceridaemia which cannot be controlled by very strict diet, omega-3 fatty acid compounds can be considered.
Hypothyroidism Children with hypothyroidism should receive adequate thyroid replacement therapy before their requirement for lipid-regulating treatment is assessed because correction of hypothyroidism itself may resolve the lipid abnormality. Untreated hypothyroidism increases the risk of myositis with lipid-regulating drugs.
CSM advice (muscle effects)
The CSM has advised that rhabdomyolysis associated with lipid-regulating drugs such as the fibrates and statins appears to be rare (approx. 1 case in every 100 000 treatment years) but may be increased in those with renal impairment and possibly in those with hypothyroidism (see also notes above).
Concomitant treatment with drugs that increase plasma-statin concentration increase the risk of muscle toxicity; concomitant treatment with a fibrate and a statin may also be associated with an increased risk of serious muscle toxicity.
Statins
The statins (atorvastatin, pravastatin, and simvastatin) competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in cholesterol synthesis, especially in the liver. They are more effective
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than other classes of drugs in lowering LDL-cholesterol but less effective than the fibrates in reducing triglycerides. Statins also increase concentrations of HDL-cholesterol.
Statins reduce cardiovascular disease events and total mortality in adults, irre-spective of the initial cholesterol concentration.
Cautions Statins should be used with caution in those with a history of liver disease or with a high alcohol intake (use should be avoided in active liver disease). Hypothyroidism should be managed adequately before starting treat-ment with a statin (see p. 159). Liver-function tests should be carried out before and within 1–3 months of starting treatment and thereafter at intervals of 6 months for 1 year, unless indicated sooner by signs or symptoms suggestive of hepatotoxicity. Treatment should be discontinued if serum transaminase concen-tration rises to, and persists at, 3 times the upper limit of the reference range.
Statins should be used with caution in those with risk factors for myopathy or rhabdomyolysis; children or their carers should be advised to report unexplained muscle pain (see Muscle Effects below). Statins should be avoided in acute porphyria (section 9.8.2).Interactions: Appendix 1 (statins)
Contra-indications Statins are contra-indicated in active liver disease (or per-sistently abnormal liver function tests), in pregnancy (adequate contraception required during treatment and for 1 month afterwards), and during breast-feeding.
Side-effects Statins can cause various muscular side-effects, including myositis, which can lead to rhabdomyolysis. Muscular effects are rare but often significant (see below and CSM advice (Muscle effects), p. 159). Statins can cause gastro-intestinal disturbances, and very rarely pancreatitis. They can also cause altered liver function tests, and rarely hepatitis and jaundice; hepatic failure has been reported very rarely. Other side-effects include sleep disturbance, headache, dizziness, depression, paraesthesia, hypoaesthesia, asthenia, peripheral neuro-pathy, amnesia, fatigue, sexual dysfunction, thrombocytopenia, arthralgia, visual disturbance, alopecia, and hypersensitivity reactions (including rash, pruritus, urticaria, and very rarely lupus erythematosus-like reactions). In very rare cases statins can cause interstitial lung disease; if patients develop symptoms such as dyspnoea, cough, and weight loss, they should seek medical attention.
Muscle effectsMyalgia, myositis, and myopathy have been reported with the statins; if myopathy is suspected and creatine kinase is markedly elevated (more than 5 times upper limit of normal), treatment should be discontinued; in children at high risk of muscle effects, a statin should not be started if creatine kinase is elevated. Children at high risk of myopathy include those with a personal or family history of muscular disorders, previous history of muscular toxicity or liver disease (see also CSM advice, p. 159). There is also an increased incidence of myopathy if the statins are given with a fibrate, with lipid-lowering doses of nicotinic acid, or with immunosuppressants such as ciclosporin;
close monitoring of liver function and, if symptomatic, of creatine kinase is required in patients receiving these drugs. Rhabdomyolysis with acute renal impairment secondary to myoglobinuria has also been reported.
Counselling Advise children or their carers to report promptly unexplained muscle pain, tenderness, or weakness.
ATORVASTATIN
Cautions see notes above; also haemorrhagic stroke
Hepatic impairment avoid in active liver disease or unexplained persistent elevations in serum transaminases
Contra-indications see notes above Pregnancy avoid—congenital anomalies reported; decreased synthesis of cholesterol pos-sibly affects fetal development
Breast-feeding manufacturer advises avoid—no information available
Side-effects see notes above; also chest pain;
back pain; pruritus; less commonly anorexia, malaise, weight gain, hypoglycaemia, hyperglyc-aemia, and tinnitus; rarely cholestatic jaundice and peripheral oedema; very rarely taste
distur-bances, gynaecomastia, hearing loss, Stevens-Johnson syndrome, and toxic epidermal necro-lysis
Indication and dose
Hyperlipidaemia including familial hyper-cholesterolaemia
. By mouth
Child 10–17 yearsinitially 10 mg once daily, increased if necessary, at intervals of at least 4 weeks to usual max. 20 mg once daily Child 17–18 yearsinitially 10 mg once daily, increased if necessary, at intervals of at least 4 weeks to max. 80 mg once daily
NoteReduced dose required with concomitant ciclos-porin, clarithromycin, or itraconazole—seek specialist advice
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Lipitorc(Pfizer)A
Tablets,all f/c, atorvastatin (as calcium trihydrate) 10 mg, net price tab pack = £18.03; 20 mg,
28-tab pack = £24.64; 40 mg, 28-28-tab pack = £28.21;
80 mg, 28-tab pack = £28.21. Counselling, muscle effects, see notes above
PRAVASTATIN SODIUM
Cautions see notes above
Hepatic impairment avoid in active liver disease or unexplained persistent elevations in serum transaminases
Renal impairment start with lower doses in moderate to severe impairment
Contra-indications see notes above Pregnancy avoid—congenital anomalies reported; decreased synthesis of cholesterol pos-sibly affects fetal development
Breast-feeding small amounts present in breast milk—manufacturer advises avoid
Side-effects see notes above; less commonly abnormal urination (including dysuria, nocturia, and frequency); very rarely fulminant hepatic necrosis
Licensed use licensed in children over 8 years for familial hypercholesterolaemia
Indication and dose
Hyperlipidaemia including familial hyper-cholesterolaemia
. By mouth
Child 8–14 years10 mg once daily at night, adjusted at intervals of at least 4 weeks to max.
20 mg once daily at night
Child 14–18 years10 mg once daily at night, adjusted at intervals of at least 4 weeks to max.
40 mg once daily at night
Pravastatin(Non-proprietary)A
Tablets, pravastatin sodium 10 mg, net price 28-tab pack = £1.73; 20 mg, 28-tab pack = £2.22; 40 mg, 28-tab pack = £2.77
Counsellingmuscle effects, see notes above
Lipostatc(Squibb)A
Tablets, all yellow, pravastatin sodium 10 mg, net price 28-tab pack = £15.05; 20 mg, 28-tab pack =
£27.61; 40 mg, 28-tab pack = £27.61. Counselling, muscle effects, see notes above
SIMVASTATIN
Cautions see notes above
Hepatic impairment avoid in active liver disease or unexplained persistent elevations in serum transaminases
Renal impairment doses above 5 mg daily (10 mg daily in children over 10 years) should be used with caution if estimated glomerular filtration rate less than 30 mL/minute/1.73 m2
Contra-indications see notes above Pregnancy avoid—congenital anomalies reported; decreased synthesis of cholesterol pos-sibly affects fetal development
Breast-feeding manufacturer advises avoid—no information available
Side-effects see notes above; also rarely anaemia Licensed use not licensed for use in children Indication and dose
Hyperlipidaemia including familial hyper-cholesterolaemia
. By mouth
Child 5–10 yearsinitially 5 mg at night increased, if necessary, at intervals of at least 4 weeks to max. 20 mg at night
Child 10–18 yearsinitially 10 mg at night increased, if necessary, at intervals of at least 4 weeks to max. 40 mg at night
NoteReduced dose required with concomitant ciclosporin, danazol, fibrates, amiodarone, diltiazem, or verapamil—seek specialist advice
Simvastatin(Non-proprietary)A
Tablets, simvastatin 10 mg, net price 28-tab pack = 85p; 20 mg, 28-tab pack = 95p; 40 mg, 28-tab pack
= £1.37; 80 mg, 28-tab pack = £2.94. Counselling, muscle effects, see notes above
Brands include Simvadorc
Zocorc(MSD)A
Tablets, all f/c, simvastatin 10 mg (peach), net price 28-tab pack = £18.03; 20 mg (tan), 28-tab pack =
£29.69; 40 mg (red), 28-tab pack = £29.69; 80 mg (red), 28-tab pack = £29.69. Counselling, muscle effects, see notes above
Bile acid sequestrants
Colestyramine (cholestyramine) and colestipol are bile acid sequestrants used in the management of hypercholesterolaemia. They act by binding bile acids, preventing their reabsorption; this promotes hepatic conversion of cholesterol into bile acids; the resultant increased LDL-receptor activity of liver cells increases the clearance of LDL-cholesterol from the plasma. Thus both com-ATORVASTATIN (continued)
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pounds effectively reduce LDL-cholesterol but can aggravate hypertriglyceridae-mia. Bile acid sequestrants are not well tolerated and compliance with treatment is poor, therefore they are rarely used in children.
Cautions Bile acid sequestrants interfere with the absorption of fat-soluble vitamins; supplements of vitamins A, D and K may be required when treatment is prolonged and the child’s growth and development should be monitored.
Interactions: Appendix 1 (bile acid sequestrants).
Side-effects As bile acid sequestrants are not absorbed, gastro-intestinal side-effects predominate. Constipation is common, but diarrhoea has occurred, as have nausea, vomiting, and gastro-intestinal discomfort. Hypertriglyceridaemia may be aggravated. An increased bleeding tendency has been reported due to hypoprothrombinaemia associated with vitamin K deficiency.
Counselling Other drugs should be taken at least 1 hour before or 4–6 hours after bile acid sequestrants to reduce possible interference with absorption.
COLESTYRAMINE
(Cholestyramine) Cautions see notes above
Hepatic impairment interferes with absorption of fat-soluble vitamins and may aggravate mal-absorption in primary biliary cirrhosis; likely to be ineffective in complete biliary obstruction Pregnancy use with caution—drug not absorbed but may cause fat soluble vitamin deficiency on prolonged use
Breast-feeding use with caution—drug not absorbed but may cause fat soluble vitamin defi-ciency on prolonged use
Contra-indications complete biliary obstruction (not likely to be effective)
Side-effects see notes above; intestinal obstruc-tion reported rarely and hyperchloraemic aci-dosis reported on prolonged use
Licensed use licensed in children over 6 years to reduce cholesterol; see also section 1.9.2 Indication and dose
Familial hypercholesterolaemia . By mouth
Child 6–12 yearsinitially 4 g once daily increased to 4 g up to 3 times daily according to response
Child 12–18 yearsinitially 4 g once daily increased by 4 g at weekly intervals to 12–24 g daily in 1–4 divided doses, then adjusted according to response; max. 36 g daily
Cholestatic pruritussection 1.9.2
Diarrhoeasection 1.9.2
Administration The contents of each sachet should be mixed with at least 150 mL of water or other suitable liquid such as fruit juice, skimmed milk, thin soups, and pulpy fruits with a high moisture content; total daily dose may be given as a single dose if tolerated
Colestyramine(Non-proprietary)A
Powder, sugar-free, colestyramine (anhydrous) 4 g/
sachet, net price 50-sachet pack = £18.20.
Label: 13, counselling, avoid other drugs at same time (see notes above)
Excipientsmay include aspartame (section 9.4.1)
Questranc(Bristol-Myers Squibb)A
Powder, colestyramine (anhydrous) 4 g/sachet, net price 50-sachet pack = £11.42. Label: 13, counsel-ling, avoid other drugs at same time (see notes above)
Excipientsinclude sucrose 3.79g/sachet
Questran Lightc(Bristol-Myers Squibb)A Powder, sugar-free, colestyramine (anhydrous) 4 g/
sachet, net price 50-sachet pack = £16.99.
Label: 13, counselling, avoid other drugs at same time (see notes above)
Excipientsinclude aspartame (section 9.4.1)
COLESTIPOL HYDROCHLORIDE
Cautions see notes above
Pregnancy use with caution—drug not absorbed but may cause fat soluble vitamin deficiency on prolonged use
Breast-feeding use with caution—drug not absorbed but may cause fat soluble vitamin defi-ciency on prolonged use
Side-effects see notes above
Licensed use not licensed for use in children
Indication and dose
Familial hypercholesterolaemia . By mouth
Child 12–18 yearsinitially 5 g 1–2 times daily increased if necessary in 5-g increments at intervals of 1 month to max. of 30 g daily in 1–2 divided doses
Administration The contents of each sachet should be mixed with at least 100 mL of water or other suitable liquid such as fruit juice, skimmed milk, thin soups, cereals, yoghurt, and pulpy fruits with a high moisture content; total daily dose may be given as a single dose if tolerated
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Colestidc(Pharmacia)A
Granules, yellow, colestipol hydrochloride 5 g/
sachet, net price 30 sachets = £15.05. Label: 13, counselling, avoid other drugs at same time (see notes above)
Colestid Orange, granules, yellow/orange, colesti-pol hydrochloride 5 g/sachet, with aspartame, net price 30 sachets = £15.05. Label: 13, counselling, avoid other drugs at same time (see notes above)
Ezetimibe
Ezetimibe inhibits the intestinal absorption of cholesterol. It is given in combina-tion with a statin or alone if a statin is inappropriate. If ezetimibe is used in combination with a statin, there is an increased risk of rhabdomyolysis (see also CSM advice on p. 159).
EZETIMIBE
Cautions interactions: Appendix 1 (ezetimibe) Hepatic impairment avoid in moderate and severe impairment—may accumulate Pregnancy manufacturer advises use only if potential benefit outweighs risk—no information available
Contra-indications
Breast-feeding present in milk in animal stu-dies—manufacturer advises avoid
Side-effects gastro-intestinal disturbances; head-ache, fatigue; myalgia; rarely arthralgia, hyper-sensitivity reactions (including rash, angioedema, and anaphylaxis), hepatitis; very rarely pancreat-itis, cholelithiasis, cholecystpancreat-itis, thrombocytope-nia, raised creatine kinase, myopathy, and rhab-domyolysis
Indication and dose
Adjunct to dietary measures and statin treat-ment in primary hypercholesterolaemia and homozygous familial hypercholesterolaemia (ezetimibe alone in primary hypercholesterol-aemia if statin inappropriate or not tolerated) adjunct to dietary measures in homozygous sitosterolaemia
Child 10–18 years10 mg once daily
Ezetrolc(MSD, Schering-Plough)T A
Tablets, ezetimibe 10 mg, net price 28-tab pack =
£26.31
Fibrates
Bezafibrate and fenofibrate act mainly by decreasing serum triglycerides; they have variable effects on LDL-cholesterol. Fibrates may reduce the risk of cor-onary heart disease in those with low HDL-cholesterol or with raised triglycerides.
Fibrates can cause a myositis-like syndrome, especially in children with impaired renal function. Also, combination of a fibrate with a statin increases the risk of muscle effects (especially rhabdomyolysis) and should be used with caution (see CSM advice, p. 159).
There is limited evidence to support their use in children and they should only be considered if treatment with a statin and a bile acid sequestrant is unsuccessful or contra-indicated.
BEZAFIBRATE
Cautions correct hypothyroidism before initiating treatment (see Lipid-regulating Drugs, p. 159);
see under Myotoxicity below;interactions:
Appendix 1 (fibrates)
MyotoxicitySpecial care needed in patients with renal disease, as progressive increases in serum creatinine concentration or failure to follow dosage guidelines may result in myotoxicity (rhabdomyolysis); discontinue if myotoxicity suspected or creatine kinase concentration increases significantly
Hepatic impairment avoid in severe impairment Renal impairment reduce dose if estimated glomerular filtration rate 15–60 mL/minute/
1.73 m2; avoid if estimated glomerular filtration rate less than 15 mL/minute/1.73 m2; see also Myo-toxicity above
Contra-indications hypoalbuminaemia, primary biliary cirrhosis, gall bladder disease, nephrotic syndrome
Pregnancy embryotoxicity in animal studies—
manufacturers advise avoid
Breast-feeding manufacturer advises avoid—no information available
Side-effects gastro-intestinal disturbances, ano-rexia; less commonly cholestasis, weight gain, dizziness, headache, fatigue, drowsiness, renal impairment, raised serum creatinine (unrelated to renal impairment), erectile dysfunction, myo-toxicity (with myasthenia or myalgia)—particular risk in renal impairment (see Cautions), urticaria, pruritus, photosensitivity reactions; very rarely gallstones, hypoglycaemia, anaemia, leucopenia, COLESTIPOL HYDROCHLORIDE (continued)
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thrombocytopenia, increased platelet count, alo-pecia, Stevens-Johnson syndrome, and toxic epidermal necrolysis
Licensed use not licensed for use in children Indication and dose
Hyperlipidaemia including familial hyper-cholesterolaemia(on specialist advice only) . By mouth
Child 10–18 years200 mg once daily adjusted according to response to max. 200 mg 3 times daily
Bezafibrate(Non-proprietary)A
Tablets, bezafibrate 200 mg, net price 100-tab pack
= £11.23. Label: 21 Bezalipc(Roche)A
Tablets, f/c, bezafibrate 200 mg, net price 100-tab pack = £9.15. Label: 21
FENOFIBRATE
Cautions see under Bezafibrate; liver function tests recommended every 3 months for first year (discontinue treatment if significantly raised) Hepatic impairment avoid in severe impairment Renal impairment reduce dose if estimated glomerular filtration rate less than 60 mL/minute/
1.73 m2; avoid if estimated glomerular filtration rate less than 15 mL/minute/1.73 m2
Contra-indications gall bladder disease; photo-sensitivity to ketoprofen
Pregnancy embryotoxicity in animal studies—
manufacturer advises avoid
Breast-feeding manufacturer advises avoid—no information available
Side-effects see under Bezafibrate; also very rarely hepatitis, pancreatitis, and interstitial pneumopathies
Licensed use LipantilcMicro 67 is licensed for use in children with hypercholesterolaemia Indication and dose
Hyperlipidaemias including familial hyper-cholesterolaemia(on specialist advice only) . By mouth
Child 4–15 years1 capsule/20 kg body-weight daily
Child 15–18 yearsinitially 3 capsules daily in divided doses; usual range 2-4 capsules daily
Lipantilc(Solvay)A
LipantilcMicro 67 capsules, yellow, fenofibrate (micronised) 67 mg, net price 90-cap pack = £23.30.
Label: 21