BNF for Children 2011-2012

126 2.12 Lipid-regulating drugs BNFC 2011–20122 Cardiovascular systemEzetimibe can be used alone when statins are nottolerated, or in combination with a statin when a highdosestatin fails to control cholesterol concentrationadequately.Bile acid sequestrants are also available but tolerabilityof and compliance with these drugs is poor, and theiruse is declining.Evidence for the use of a fibrate (bezafibrate or fenofibrate)in children is limited; fibrates should be consideredonly if dietary intervention and treatment with astatin and a bile acid sequestrant is unsuccessful orcontra-indicated.In hypertriglyceridaemia which cannot be controlled byvery strict diet, omega-3 fatty acid compounds can beconsidered.StatinsThe statins (atorvastatin, fluvastatin, pravastatin,rosuvastatin 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 thanother classes of drugs in lowering LDL-cholesterol butless effective than the fibrates in reducing triglycerides.Statins also increase concentrations of HDL-cholesterol.Statins reduce cardiovascular disease events and totalmortality in adults, irrespective of the initial cholesterolconcentration.Cautions Hypothyroidism should be managed adequatelybefore starting treatment with a statin (seeHypothyroidism, p. 125). Statins should be used withcaution in those with a history of liver disease or with ahigh alcohol intake—see also Hepatic Impairment,below. There is little information available on a rationalapproach to liver-function monitoring; however, a NICEguideline 1 suggests that liver enzymes should be measuredbefore treatment, and repeated within 3 monthsand at 12 months of starting treatment, unless indicatedat other times by signs or symptoms suggestive ofhepatotoxicity. Those with serum transaminases thatare raised, but less than 3 times the upper limit of thereference range, should not be routinely excluded fromstatin therapy. Those with serum transaminases of morethan 3 times the upper limit of the reference rangeshould discontinue statin therapy. Statins should beused with caution in those with risk factors for myopathyor rhabdomyolysis; children or their carers shouldbe advised to report unexplained muscle pain (seeMuscle Effects below). Creatine kinase concentrationshould be measured in children before treatment and ifunexplained muscle pain occurs. Statins should beavoided in acute porphyria (section 9.8.2). Interactions:Appendix 1 (statins).Hepatic impairment Statins should be used withcaution in those with a history of liver disease andavoided in active liver disease or when there are unexplainedpersistent elevations in serum transaminases.1. NICE clinical guideline 67 (May 2008). Lipid Modification—Cardiovascularrisk assessment and the modificationof blood lipids for the primary and secondary prevention ofcardiovascular diseasePregnancy Statins should be avoided in pregnancy ascongenital anomalies have been reported and thedecreased synthesis of cholesterol possibly affectsfetal development. Adequate contraception is requiredduring treatment and for 1 month afterwards.Breast-feeding The manufacturers of atorvastatin,fluvastatin, rosuvastatin, and simvastatin advise avoidinguse in mothers who are breast-feeding as there is noinformation available. The manufacturers of pravastatinadvise against use in breast-feeding mothers as a smallamount of drug is present in breast milk.Side-effects Statins can cause various muscular sideeffects,including myopathy, myositis, and rhabdomyolysis.Muscular effects are rare but often significant (seeMuscle Effects below). Statins can cause gastro-intestinaldisturbances, and very rarely pancreatitis. Theycan also cause altered liver function tests, and rarelyhepatitis and jaundice; hepatic failure has been reportedvery rarely. Other side-effects include sleep disturbance,headache, dizziness, depression, paraesthesia,hypoaesthesia, asthenia, peripheral neuropathy, amnesia,fatigue, sexual dysfunction, thrombocytopenia,arthralgia, visual disturbance, alopecia, and hypersensitivityreactions (including rash, pruritus, urticaria, andvery rarely lupus erythematosus-like reactions). In veryrare cases statins can cause interstitial lung disease; ifchildren develop symptoms such as dyspnoea, cough,and weight loss, they should seek medical attention.Muscle effects Myalgia, myositis, myopathy, and rarely rhabdomyolysishave been reported with the statins; if myopathy issuspected and creatine kinase is markedly elevated (more than5 times upper limit of reference range), or muscular symptomsare severe, treatment should be discontinued; in children atincreased risk of muscle effects, a statin should not be started ifcreatine kinase is elevated. Children at increased risk of myopathyinclude females and those with a personal or familyhistory of muscular disorders, previous history of musculartoxicity, those with a high alcohol intake, renal impairment,and, hypothyroidism (see Hypothyroidism, p. 125). There isalso an increased incidence of myopathy if a statin is given at ahigh dose or given with a fibrate, with lipid-lowering doses ofnicotinic acid, or with drugs that increase the plasma-statinconcentration, such as ciclosporin; close monitoring of liverfunction and, if symptomatic, of creatine kinase is required inchildren receiving these drugs. Rhabdomyolysis with acuterenal impairment secondary to myoglobinuria has also beenreported.Counselling Advise children or their carers to reportpromptly unexplained muscle pain, tenderness, orweakness.ATORVASTATINCautions see notes above; also haemorrhagic strokeHepatic impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also chest pain; backpain; pruritus; less commonly anorexia, malaise,weight gain, hypoglycaemia, hyperglycaemia, andtinnitus; rarely cholestatic jaundice and peripheraloedema; very rarely taste disturbances, gynaecomastia,hearing loss, Stevens-Johnson syndrome, andtoxic epidermal necrolysis