Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases (JCS 2012) – Digest Version

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Circulation Journal JCS GUIDELINES Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Guidelines for Drug Therapy in Pediatric Patients With Cardiovascular Diseases (JCS 2012) – Digest Version – JCS Joint Working Group

Table of Contents Introduction∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 507 II. Cardiovascular Complications of Kawasaki General∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 508 Disease∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 511 I. Purpose of the Present Guideline Documents∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 508 III. Hyperlipidemia∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 515 II. Special Consideration of Clinical Trials in Children∙∙∙∙∙∙∙∙∙∙∙ 508 IV. Arrhythmia∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 516 III. Approval by Medical and Pharmaceutical Public V. Hypertension∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 517 Knowledge∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 508 VI. Hypotension∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 519 IV. Clinical Development of Pediatric Cardiovascular VII. Pulmonary Arterial Hypertension∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 520 Drugs∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 509 VIII. Myocardial Diseases∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 521 V. Basics of In Vivo Pharmacokinetics∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 509 IX. Infective Endocarditis∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 522 VI. Developmental Changes in Pediatric X. Premature and Newborn Medicine∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 522 Pharmacokinetics∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 XI. Radionuclide Imaging∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 522 1. Neonatal and Infantile Period∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 XII. Immunosuppressive for Organ Transplantation∙∙∙∙∙∙∙∙∙∙∙∙∙ 525 2. Early Childhood and After∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 XIII. Anesthetics and Sedatives∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 525 Specific Medications∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 Summary∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 527 I. Congesive Heart Failure Medications∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 I. List of Cardiovascular Drugs for Children∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 527 1. Renin-Angiotensin-Aldosterone System Inhibitors∙∙∙∙∙ 510 References∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 531 2. β-Blockers∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 510 3. Phosphodiesterase 3 Inhibitors∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 511 (Circ J 2014; 78: 507 – 533)

Introduction

The present guideline documents were developed with a focus and influences on lactation in patients with cardiovascu- on appropriate drug therapy in pediatric patients with cardio- lar disease, vascular diseases, under the principle of “the Right drug for 4. Coronary artery complications of Kawasaki disease, and the Right pediatric patient at the Right time.” others. The reason for this effort is that it has recently become more common for not only pediatricians but also specialists in adult There are various developmental processes in childhood to cardiovascular diseases to see the following diseases and con- adulthood, such as functional development of the cardiovas- ditions: cular system and developmental changes in the liver, kidney, endocrine system and density of receptors. Therefore, the 1. Cardiovascular diseases in children and youth, therapeutic dose for children should be determined by taking 2. Adult congenital heart disease patients with arrhythmia into account their complex modifiers, other than simply age, or heart failure, and not by regarding children as “miniature adults”.1 3. Management of pregnancy and delivery, fetal therapy,

Released online December 26, 2013 Mailing address: Scientific Committee of the Japanese Circulation Society, 18F Imperial Hotel Tower, 1-1-1 Uchisaiwai-cho, Chiyoda-ku, Tokyo 100-0011, Japan. E-mail: [email protected] This English language document is a digest version of Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases reported at the Japanese Circulation Society Joint Working Groups performed in 2010–2011 (Website: http://www.j-circ.or.jp/guideline/ pdf/JCS2012_sachi_d.pdf). Joint Working Groups: The Japanese Circulation Society, The Japan Society for Transplantation, The Japanese Society of Kawasaki Disease, The Japanese Society of Pediatric Hypertension, The Japanese Society of Pediatric Hematology, The Japan Society Lipid Pediatric Conference, The Japanese Society of Pediatric Cardiology and Cardiac Surgery, The Japanese Society for Pediatric Nephrology, The Japanese Society of Pediatric Electrocardiography, The Japanese Society of Pediatric Anesthesiology, The Japan Society of Develop- mental Pharmacology and Therapeutics, The Japanese College of Cardiology, The Japan Society of Premature and Newborn Medicine, The Japanese Society of Clinical Pharmacology and Therapeutics ISSN-1346-9843 doi: 10.1253/circj.CJ-66-0083 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

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General

Indications for Drug Use in Pediatric Patients and II. Spcial Considerations of Off-Label Use Clinical Trials in Children The limitations described in the package insert as “safety in children has not been established (no clinical experience)” are generally interpreted as follows: Clinical trials of new drugs in children and youth are limited by the U.S. Food and Drug Administration (FDA) and the 1. There are no limitations about the use of the drug in European Medicines Evaluation Agency (EMEA) in terms of children at the physician’s discretion. the following: 2. Because clinical experience with the drug is limited, and therefore pharmacokinetics is unclear, the efficacy and 1. Selection of the therapeutic dose and the drug formulation safety in children are not established as they are in adults. 2. Developmental and age-related changes in human organs 3. Appropriate dosage and administration have not been 3. Unexpected effects on normal developmental process established. 4. Pharmacokinetics 4. The drug should be administered with caution. 5. Pharmacodynamics 5. Because proper usage cannot be determined, pediatric patients are not covered by the national insurance for Therefore, considering the difficulties in clinical trials and health hazards. corporate attitude toward drug development, incentives, Na- 6. However, complete prohibition of the use of the drug is tional Health Insurance (NHI) pricing formula, patent terms, not intended. and others, off-label use is necessarily frequent in children and youth, and it is often based on experience in a limited number of patients. In addition, because there are age-related limita- I. Purpose of the Present Guideline Documents tions in surgical manipulations and techniques, the importance of medical therapy is higher in this population. In most cases, Drugs used in clinical practice often do not have pediatric in- selection of the therapeutic dosage and treatment results de- dications. Only about 30~40% of recently approved drugs are rived from experience with adult patients, and sometimes permitted for pediatric use. trends in preceding use in overseas countries as well, are used However, many pediatricians use off-label drugs in their as reference information. practice when it is considered indispensable although they are Recently, guidelines of the clinical evaluation of new drugs aware that the drugs are off-label, and they use these drugs in pediatric patients have been prepared, and the movement of with caution, attaching importance to the safety as well as the new drug development for these patients has been accelerated. usefulness of the drug and the balance of risk and benefit. In recent years, it has been becoming apparent that the response to the drugs, such as warfarin, varies among children accord- III. Approval by Medical and ing to the individual’s pharmacogenetic profile. The factors Pharmaceutical Public Knowledge shown in Table 1 are involved in the pharmacokinetic vari- ability of drugs used in children. Over the past decade, it has become possible to approve some drugs for use in children without conducting additional clini-

Table 1. Factors Affecting Pharmacokinetics 1. Absorption of drugs: Modified absorption due to gastric acid pH, gastric emptying time, bile secretion, and pancreatic exocrine function 2. Body distribution: Increased concentration of free molecules due to water volume, fatty mass, blood protein concentration, and drug binding rate 3. Drug metabolism: Enhancement or attenuation of effects due to hepatic glucuronic acid conjugation and cytochrome p450 activity 4. Drug elimination: Dose adjustment is necessary, considering prolongation of half-life due to decreased renal blood flow and GFR GFR, glomerular filtration rate.

Table 2. Public Knowledge in the Medical and Pharmaceutical Fields2 1. “Approval” and “clinical experience” in overseas countries and overseas “application materials” are available. 2. “Research papers and review articles” published in overseas countries are present. 3. Research papers issued on high quality and peer reviewed journals are available (guidelines and guiding princi- ples of domestic or overseas academic societies are available). 4. Results of clinical studies by commissioned research of public research projects are available. 5. Medical and pharmaceutical “public knowledge” is applied only to drugs that have sufficient evidence (drugs that are already in wide use). 6. Novel drugs are excluded.

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Table 3. Recently Approved Cardiovascular Drugs for Pediatric Use (since January 2001 to November 2012) 1. Clinical studies conducted - Palivizumab (anti-RS virus antibody) 2. Medical and pharmaceutical public knowledge (no newly conducted clinical studies) - Immune globulin, aspirin (Kawasaki disease) - Alprostadil (PGE1-αCD) (patent ductus arteriosus dependent cyanotic heart disease) - Flecainide acetate (Tambocor) (tachyarrhythmia) - Warfarin potassium (anticoagulation) - Verapamil hydrochloride (Vasolan) (tachyarrhythmia) 3. Recently officially noticed and approved drugs - Amlodipine (Norvasc), enalapril (Renivase), lisinopril (Longes), valsartan (Diovan) for hypertension - Propranolol (Inderal) for tachyarrhythmia

αCD, α-cyclodextrin; PGE1, prostaglandin E1; RS, respiratory syncytial.

Table 4. Ontogeny of Hepatic Metabolism per Unit Organ Weight and Renal Excretion Activity in the Neonatal and Infantile Periods6 Hepatic metabolism Oxidation CYP1A2 Almost no activity at birth. Expression occurs 1~3 months after birth, and reaches the adult level at 4~5 months. CYP2C9 Low activity at birth. Activity increases after birth, and reaches an almost adult level in half of infants by 5 months after birth. CYP2C19 Low activity at birth. Expression increases slowly over a period of at least 5 months after birth. CYP2D6 Almost no activity at birth. Activity is low until 2 weeks after birth, but develops after 3 weeks according to the genotypes, showing distinct difference in activity by gene polymorphism. Activity reaches the adult level by age 10 years. CYP3A4 Low expression at birth. Increases slowly to an adult level over a period of 1~2 years after birth. CYP3A7 Expression occurs in the early embryonic period, but decreases soon after birth, reaching almost nil by 1 year after birth. Conjugation (transferase) metabolism enzymes UGT1A1 Research in humans is insufficient. UGT1A4 Expression at birth is less than 50% of the adult level, but reaches an almost adult level by about age 1.5 years. UGT1A6 Activity is low through the neonatal to infantile period. UGT2B7 Activity in the neonatal period is about 20% of the child level (at about age 10 years), and increases rapidly 2~6 months after birth. Sulfatase Activity in the neonatal period is about 70% of the adult level. N-acetylation enzyme Activity is low at birth and until 2 months after birth. Gene polymorphism-related difference is apparent 6 months after birth, and activity reaches the adult level 1~4 years after birth. Methyl transferase Activity is already in the adult level at birth.

Renal excretion Glomerular filtration rate (GFR) The rate in the neonatal period corresponds to 10~20% of the adult level, but reaches the adult level at about age 1 year. Active tubular transport The function level is low in the neonatal period, but reaches the adult level at about age 1 year, although its development is slower than glomerular development. CYP, cytochrome P450; UGT, UDP-glucuronosyltransferase.

cal studies. This is because the policy of “application based on 3,4 medical and pharmaceutical public knowledge” on the drug’s V. Basics of In Vivo Pharmacokinetics safety and efficacy was applied. Application based on public knowledge requires that the certain conditions listed in Table 2 It is generally accepted that only free or unbound form of are met (See “the handling of drugs in off-label use”, Notice drugs can reach the site of action. Therapeutic drug monitor- from the Ministry of Health, Labour and Welfare, Ken No. 4, ing (TDM) is a means of measuring drug levels in the blood. Iyakushin No. 104, issued on February 1, 1999).2 Because total (free plus bound) drug levels are measured with TDM service, caution should be exercised when drug efficacy or toxicity are interpreted in the light of measured drug levels IV. Clinical Development of in disease conditions where the plasma protein binding is al- Pediatric Cardiovascular Drugs tered as compared healthy subjects. It should also be noted that drug interactions take place at each step of in vivo phar- The cardiovascular drugs shown in Table 3 have been ap- macokinetics (i.e., absorption, distribution, metabolism and proved for pediatric use since January 2001 to November 2012. excretion).

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needed. And because the ability of these children to eliminate VI. Developmental Changes in drugs per body weight (clearance) is apparently greater than 3–6 Pediatric Pharmacokinetics that in adults, the drug requirements per body weight is up to 2-fold higher (e.g., warfarin) for this age of pediatric patients. 1. Neonatal and Infantile Period In children, values of drug clearance that are normalized by Hepatic metabolism and renal excretion of drugs is immature the body surface area proportional to the weight growth of the at birth, but they show substantial increase during the neonatal liver and kidney (values per m2) are, in many cases, similar to and infantile period. those in adults. A new formula should be created to obtain The time course of development of drug metabolism varies useful estimates of therapeutic doses for pediatric patients, according to the molecular species of drug-metabolizing en- taking into account the physiological and developmental zymes. Renal function (glomerular filtration, tubular secretion changes in pharmacokinetics. and resorption) also develops progressively after birth. The Table 4 shows the ontogeny of hepatic metabolism and drug clearance in the unit-weight of liver and kidney tissue renal excretion per unit organ weight in the neonatal and in- appears approaching those of adults at or around 2 years, and fantile period.6 Clinical studies in children should be con- the developmental increase in their organ clearance is largely ducted to determine whether the observed findings can be at- associated with that of their organ weights. tributed to developmental pharmacokinetics or differences in sensitivity. 2. Early Childhood and After As for pharmacodynamics, it has been reported that chil- In school-age children and adolescents, the ratio of the weight dren respond differently from adults for a number of drugs of the drug-eliminating organs (liver and kidneys) to the total (e.g., cyclosporine and warfarin) even when the concentration body weight is at most twice greater than that of adults. This of the drug exposed to the action site is comparable. In addi- means that these children have greater drug clearance normal- tion, some drugs (e.g., valproic acid and isoniazid) are known ized to body weight than adults. As a result, pediatric doses of to cause severe drug-induced hepatic injury at higher risks in drugs extrapolated from corresponding adult doses in body children than adults. weight basis (e.g., mg/kg) often underestimate those actually

Specific Medications

12,13 I. Congestive-Heart Failure Medications7–11 2. β-blockers (Table 7) A U.S. study of carvedilol for heart failure in children showed no significant difference between placebo group and low- or 1. Renin-Angiotensin-Aldosterone System Inhibitors high-dose carvedilol groups for the composite end point (heart (Table 5) failure outcomes).14 However, subgroup analysis demonstrated The use of renin-angiotensin-aldosterone (RAA) system in- possible beneficial effect in patients with systemic left ventri- hibitors is basic treatment for heart failure. Although these cle.15,16 Adverse reactions include bradycardia, complete atrio- drugs are not approved for pediatric heart failure, enalapril, ventricular block, and exacerbation of heart failure. Character- lisinopril, and valsartan have already been approved for hyper- istically in children, these drugs are reported to be less effective tension in children. for cardiac disease in which the right ventricle is the systemic Table 6 shows a comparison of the use of enalapril in adults ventricle (e.g., corrected transposition of the great arteries). and children/youth. In children, the first-dose phenomenon at Propranolol is approved for pediatric tachyarrhythmia in the starting of administration and adverse reactions such as Japan. cough are not common. Caution is necessary in patients with Table 8 shows a comparison of carvedilol (covered by the possible renal dysfunction. NHI) in adults and children/youth.

Table 5. Vasodilators Mechanism of Action - Inhibition of enhanced RAA system activity in heart failure Target diseases - Acute and chronic heart failure Drug type (or class) - Angiotensin-converting enzyme inhibitors: captopril, enalapril, lisinopril, cilazapril - Angiotensin receptor antagonists: losartan, valsartan, candesartan - Drugs approved for use in children and youth in Japan: Enalapril, lisinopril, and valsartan are already approved for hypertension in children. Captopril is covered by the National Health Insurance. Precautions for pregnant women and fetuses - Teratogenesis (some recent reports find that the primary disease, rather than the drug, is responsible.) - Fetal growth retardation RAA, renin-angiotensin-aldosterone.

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Table 6. Enalapril: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Acute and chronic heart failure Presence/absence of indications Off-label (Approved only Approved for hypertension) Half-life T1/2 1 hour Dosage 5~10 mg/day 0.1~0.4 mg/kg/day Dosing method 1 dose per day 1~2 doses per day Major adverse reactions Renal failure, angioedema Characteristic features in children - This drug is used in congestive heart failure, aortic regurgitation, and mitral regurgitation. - Safety has not been established. - It is recommended to start with a low dose particularly in the neonatal period. - Enalapril is covered by the NHI. - Occurrence of cough specific to ACE inhibitors is rare. ACE, angiotensin converting enzyme; NHI, National Health Insurance.

Table 7. β-blockers Mechanism of Action - Inhibition of enhanced sympathetic nerve system activity in heart failure Target diseases - Chronic heart failure Drug type (or class) - Nonselective αβ ISA (–): carvedilol, 0.2~1.0 mg/kg/day (starting at a rate of 0.1 mg/kg, two divided doses) - β selective ISA (–): bisoprolol, metoprolol - Drugs approved for use in children and youth in Japan: propranolol (approved only for tachyarrhythmia) Precautions for pregnant women and fetuses - Contraindicated for pregnant women (fetal developmental toxicity) ISA, intrinsic sympathetic activity.

Table 8. Carvedilol: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Chronic heart failure Presence/absence of indications Approved Off-label (covered by NHI) Half-life T1/2 3.6 hours (10 mg single dose administration) Dosage 5~20 mg/day 0.2~1.0 mg/kg/day (starting at a rate of 2.5 mg) (starting at a rate of 0.1 mg/kg) Dosing method 2 divided doses per day Major adverse reactions Heart failure, bradycardia, complete atrioventricular block Characteristic features in children - Reportedly effective for cardiac disease in which the left ventricle is the systemic ventricle (ineffective for systemic right ventricle in corrected transposition of the great arteries). - Safety has not been established. NHI, National Health Insurance.

3. Phosphodiesterase 3 Inhibitors17–19 demonstrated with olprinone in animal experiments, and this The mechanism of their action is inhibition of phosphodiester- should be noted to protect pregnant women and fetuses. ase (PDE) 3 that leads to increased concentrations of cAMP Table 9 shows a comparison of the use of milrinone in adults (cyclic adenosine monophosphate) and cGMP (cyclic guanosine and children/youth. monophosphate) in vascular smooth muscle cells and myocardial cells. PDE3 inhibitors are indicated for acute heart failure. Intravenous milrinone and olprinone (both covered by the II. Cardiovascular Complications of 20–21 NHI) and oral pimobendan are available. Although none of Kawasaki Disease (Tables 10~16) these are approved for pediatric use, they are used in general clinical practice. None of these drugs are approved for use in Kawasaki disease, the most common acquired heart disease in children and youth in Japan. Fetal growth retardation has been children, occurs in about 11,500 individuals annually, and 3%

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Table 9. PDE3 Inhibitor Milrinone: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Acute heart failure Presence/absence of indications Approved Off-label (covered by the NHI) Half-life T1/2 1.5 hours Dosage Initial dose 50 μg/kg Initial intravenous dose per 10 minutes can be omitted in children Maintenance dose 0.5 μg/kg/min Dosing method Bolus + continuous Continuous intravenous infusion intravenous infusion Major adverse reactions Ventricular tachycardia, deterioration of renal function, obstructive hypertrophic cardiomyopathy Characteristic features in children Safety has not been established. NHI, National Health Insurance; PDE, phosphodiesterase.

Table 10. Treatment of Coronary Artery Complications of Kawasaki Disease: Anticoagulants and Antiplatelet Drugs Mechanism of Action - Inhibition of platelet aggregation, antithrombotic action by activation of the fibrinolytic system Target diseases - Coronary artery complications of Kawasaki disease (coronary aneurysm/dilatation or coronary stenosis) Drug type (or class) - Antiplatelet drugs: acetylsalicylic acid (A), clopidogrel (P), dipyridamole (covered by the NHI) - Anticoagulants: warfarin (W), unfractionated heparin (H) - Drugs approved for use in children and youth in Japan: acetylsalicylic acid (e.g., Bayaspirin, Bufferin 81), warfarin Precautions for pregnant women and fetuses - Teratogenic (W) transplacental and intrapartum hemorrhage increased (A, P, W, H). Transfer into breast milk (A, W, P). - Should not be administered to pregnant women within 12 weeks of due date. Teratogenicity in an earlier period of pregnancy found in animal experiments. - Breast-feeding should be avoided because of transfer into breast milk. - There is risk of fetal death due to bleeding tendency and maternal abnormal bleeding at the time of delivery.

- Should not be administered to patients on vitamin K2 therapy for the treatment of osteoporosis. NHI, National Health Insurance.

Table 11. Acetylsalicylic Acid: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Kawasaki disease (including cardiovascular complications of Kawasaki disease) Presence/absence of indications Approved Half-life T1/2 >20 hours Dosage 1 tablet (81 or 100 mg)/day 3~5 mg/kg/day Dosing method 1 dose per day Major adverse reactions Shock, bleeding, mucocutaneous ocular syndrome, induced asthmatic attacks, peptic ulcer, aplastic anemia, thrombocytopenia Characteristic features in children If chicken pox or influenza has infected in patients with Kawasaki disease who are younger than 15 years old, administration should be discontinued in principle (on concern that acute encephalopathy, particularly Reye’s syndrome, may occur)

of these patients have coronary artery sequelae in Japan. Tables 11,12, and 13 show a comparison of the use of as- Table 10 shows treatments for coronary artery complica- pirin, clopidogrel, and warfarin, respectively, in adults and tions of Kawasaki disease using antiplatelet and anticoagulant children/youth. drug therapy. Long-term antiplatelet or anticoagulant drug When a concomitant coronary aneurysm is present, it is therapy is often required for coronary artery complications, highly likely that thrombotic obstruction occurring in the an- particularly when a concomitant giant aneurysm (at least 6 mm eurysm will result in acute myocardial infarction. Therefore, in diameter) is present. acute thrombolytic therapy is attempted intravenously in chil-

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Table 12. Clopidogrel: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Kawasaki disease (after catheterization for cardiovascular complications) Presence/absence of indications Approved Off-label Half-life T1/2 About 7 hours Dosage 1 tablet (75 mg)/day 1 mg/kg/day* Dosing method 1 dose per day Major adverse reactions - Bleeding, gastric/duodenal ulcer, hepatic dysfunction, interstitial pneumonia, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, and other conditions - Caution is necessary for bleeding tendency in use with aspirin. Precautions for pregnant women and fetuses: - Safety has not been established. - Breast-feeding should be avoided because of possible transfer into breast milk. *0.2 mg/kg/day is recommended for infant 0~24 months of age by PICOLO (Platelet Inhibition in Children On cLOpi- dogrel) trial.22

Table 13. Warfarin: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Coronary artery complications of Kawasaki disease (with concomitant giant aneurysm) Presence/absence of indications Approved Half-life T1/2 55 hours (at 5 mg administration) Dosage 1~5 mg/day 0.05~0.12 mg/kg/day (PT/INR: 1.6~2.5, or thrombo-test: 10~25%) Dosing method 1 dose per day Major adverse reactions Bleeding, cutaneous necrosis, hepatic dysfunction, and other conditions

Vitamin K2 preparations reduce the drug effect, whereas hypnosedative drugs, anticonvulsants, antipyretic analgesics, psychoneurotic drugs, antiarrhythmic drugs, antibiotics, antifungal drugs, clopidogrel, ticlopidine, bucolome, and others, enhance the drug effect. PT/INR, prothrombin time-international normalized ratio.

Table 14. Thrombolytic Therapy for Thrombotic Occlusion of Coronary Aneurysm in Kawasaki Disease Mechanism of Action - Activation of fibrinolytic enzyme system convert plasminogen on the thrombi into plasmin, and the fibrinolytic phenomenon occurs in the produced fibrinogen, resulting in lysis of the thrombi. Target diseases - Lysis of coronary thrombosis in acute myocardial infarction (within 6 hours of onset) - Lysis of thrombosis in coronary aneurysm in Kawasaki disease Drug type (or class) - First-generation thrombolytic drug: urokinase (U) - Second-generation thrombolytic drug: alteplase (A), recombinant t-PA preparation - Third-generation thrombolytic drug: monteplase (M), recombinant modified t-PA preparation, domestic only - IVH drugs approved for use in children and youth in Japan: None. Safety and usefulness have not been established. Characteristic features in children - Safety and usefulness in children with acute myocardial infarction have not been established. Precautions for pregnant women and fetuses - Reports of fetal death in animal experiments (U, A, M). Reports of embryonal and fetal deaths in rabbits given high doses. Abruptio placentae due to the fibrinolytic action of the drug may be possible. - Half-life alteplase T1/2α: 6.3±2.2 min, T1/2β: 84.2±47.7 min - Dosage alteplase: 290,000~435,000 IU/kg (0.5~0.75 mg/kg) by intravenous route. Administer 10% of the total dose rapidly over 1~2 min and infuse the reminder over 1 hour. The recommended dose of alteplase is 0.1~0.6 mg/kg/h for 6 hours in ACCP guidelines.23 Major adverse reactions - Serious bleeding including cerebral hemorrhage, hemorrhagic cerebral infarction, arrhythmias, cardiac rupture, anaphylactic reaction - Contraindicated, as a rule, for patients who have a history of cerebral infarction, transient ischemic attack, other neurological disorder, or hypertension. ACCP, American College of Chest Physicians; t-PA, tissue plasminogen activator.

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Table 15. Prevention of Ischemic Heart Disease as the Coronary Artery Complications of Kawasaki Disease Mechanism of Action - Decrease of cardiac work, reduction of pre- and afterload, and increase of coronary blood flow Target diseases - Angina associated with coronary artery complications of Kawasaki disease Drug type (or class) - β-blockers: metoprolol (M), carvedilol (C) (covered by the NHI only for chronic heart failure) - Calcium channel blockers: nifedipine (covered by the NHI) (N), amlodipine (A), diltiazem (D) - Nitrates: isosorbide dinitrate (I), nitroglycerin (NT), nicorandil (NC) (hybrid of nitrate and ATP-sensitive potassium channel opener) - Drugs approved for use in children and youth in Japan: None Precautions for pregnant women and fetuses - Transfer into breast milk (M, C, N, A, D, I, NT), teratogenicity (N, D) ATP, adenosine triphosphate; NHI, National Health Insurance.

Table 16. Isosorbide Dinitrate: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Angina due to cardiovascular complications of Kawasaki disease Presence/absence of indications Approved Off-label Half-life T1/2 55 min (5 mg oral) Dosage, Sublingual 5~10 mg per dose Converted to amount per body weight dosing method Spray 1 push of spray 1 push of spray (1.25 mg) per dose (junior high school age or older) Adhesive patch 1 sheet per 24~48 hours Converted to amount per body weight Major adverse reactions Vertigo, hypotension, headache, nausea, vomiting, rash, and other conditions Phosphodiesterase (PDE) 3 inhibitors are contraindicated for coadministration. Diuretics, nitrates, and nitrite esters require precautions for coadministration.

Table 17. Antihyperlipidemic Drugs Mechanism of Action - Inhibition of intracellular cholesterol (CH) production, inhibition of absorption and acceleration of excretion from small intestine Target diseases - Familial hypercholesterolemia homozygote-apheresis (heterozygotes are limited in children) - Autosomal recessive hypercholesterolemia (ARH) accompanied by xanthoma, β-sitosterolemia, and other conditions Drug type - Statins: pravastatin, sinvastatin, fluvastatin, atruvastatin, pitavastatin, rosuvastatin - Non-statins: colestimide, ezetimibe - Drugs approved for use in children and youth in Japan: None Precautions for pregnant women and fetuses - Statins require careful administration to women who wish to have a baby because they cause fetal anomaly.

Table 18. Drug Therapy for Pediatric Arrhythmias Mechanism of Action - Inhibition of cardiac conduction system by sodium (Na) channel, β receptor, potassium (K) channel, and calcium (Ca) channel blockade Target diseases - Tachyarrhythmias (paroxysmal atrial fibrillation/flutter, paroxysmal supraventricular, ventricular) Drug type (or class) - Na channel blockers (I): disopyramide* (Ia), lidocaine* (Ib), flecainide (Ic) - β receptor blockers (II): propranolol, atenolol*, nadolol, metoprolol, landiolol* - K channel blockers (III): amiodarone, sotalol, nifekalant - Ca channel blockers (IV): verapamil, diltiazem, bepridil - Drugs approved for use in children and youth in Japan: flecainide, verapamil, propranolol Drugs with an asterisk (*) are covered by the National Health Insurance, as are pilsicainide and mexiletine.

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Table 19. Flecainide: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Ventricular tachyarrhythmias, Tachyarrhythmias paroxysmal atrial fibrillation/flutter (paroxysmal supraventricular, ventricular, paroxysmal atrial fibrillation/flutter) Presence/absence of indications Approved Half-life T1/2 12 hours About 8 hours for age 1~12 years 11 hours for age <1 year, age ≥12 years Intravenous drug 1~2 mg/kg by slow infusion for 10 min 1~2 mg/kg or 100~150 mg/m2 by slow infusion Oral drug 100~200 mg/day 3~5 mg/kg/day Dosing method 2 divided doses per day 2~3 divided doses per day Major adverse reactions Palpitations, bradycardia, atrial fibrillation, itching, rash, chest discomfort, vertigo, headache, nausea, abdominal pain, diplopia, photophobia, abnormal vision

Table 20. Verapamil: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Atrial fibrillation/flutter, paroxysmal supraventricular tachycardia Presence/absence of indications Approved Half-life T1/2 2.8~7.4 hours Unknown Intravenous drug 5 mg 0.1~0.2 mg/kg Dilute and infuse slowly over more than 5 min. (Do not exceed 5 mg per dose) Oral drug 120~240 mg/day 3~6 mg/kg/day (Do not exceed 240 mg) Dosing method 3 divided doses per day Major adverse reactions Hypotension, premature ventricular contraction, sinus arrest, atrioventricular block, bradycardia, premature supraventricular contraction, ventricular tachycardia, bundle branch block, sinoatrial block, transient cardiac arrest, headache, facial hot flashes Characteristic features in children Neonates and infants are highly sensitive to calcium channel blockers and are at high risk for developing bradycardia, cardiac arrest, and other serious conditions.

Table 21. Antihypertensive Drugs for High Blood Pressure in Children (Calcium Channel Blockers) Mechanism of Action - Blocking calcium ion channel and relaxing the smooth muscle cells of peripheral blood vessels Target diseases - Hypertension (essential, renal, hypertensive emergency) Drug type (or class) - First-generation dihydropyridines: nifedipine*, nicardipine, perdipine hydrochloride - Third-generation dihydropyridines: amlodipine - Verapamil, diltiazem Drugs approved for use in children and youth in Japan: amlodipine (approved for children aged 6 or older) Precautions for pregnant women and fetuses - Teratogenesis (nifedipine), increased fetal death, inhibition of body weight gain (nicardipine) - Prolonged gestational period and duration of labor (amlodipine) The drug with an asterisk (*) is covered by National Health Insurance.

dren as it is in adult patients, although the agents are off-label 26,30 for children. This treatment is chosen particularly when emer- III. Hyperlipidemia (Table 17) gency cardiac catheterization is difficult in infants (Table 14). Prevention of myocardial ischemia is extremely important Antihyperlipidemic drugs may be used for the treatment of in patients who have coronary artery aneurysm (Tables 15 and familial hyperlipidemia in children, taking the growth of the 16).23–29 vascular wall in childhood into due consideration (Table 17). Particular caution is necessary if the patient is a young girl.

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Table 22. Amlodipine: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Hypertension Presence/absence of indications Approved Approved for use in children aged 6 years or older Half-life T1/2 39 hours Comparable to adults Dosage 2.5~5 mg/day (maximum 5 mg) 2.5 mg/day (maximum 5 mg) for children aged 6 years or older Dosing method 1 dose per day Major adverse reactions Palpitations, headache, facial hot flashes, atrioventricular block Characteristic features in children - Daily doses exceeding 5 mg have not been studied in children. - The dosage due to be approved in August 2012 was expressed in “mg/day”, but not in “mg/kg/day”. - The dose described in the guidelines of ESH 200936 was “0.06~0.3 mg/kg/day, 1 dose per day”. ESH, European Society of Hypertension.

Table 23. Nifedipine: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Essential hypertension, renal hypertension Presence/absence of indications Approved Off-label (covered by the NHI) Half-life T1/2 3.51±0.60 hour (slow-release) Unknown Dosage 10~20 mg per dose (slow-release) 0.25~0.5 mg/kg/day (slow-release) maximum 3 mg/kg/day up to 60 mg/day Dosing method Twice a day Once or twice a day Major adverse reactions Palpitations, headache, facial hot flashes, edema, erythroderma Characteristic features in children - Because nifedipine (ordinary form) causes rapid and short-time pressure decrease and changes in hemodynamics in hypertensive adults, the use as an antihypertensive drug is not recommended (JSH 2009).39 - Some reports indicate that use of this drug for severe hypertension is effective in children at a low dose of 0.25 mg/kg or less. However, such usage is not recommended at present if other drugs easier to adjust are available. JSH, Japanese Society of Hypertension; NHI, National Health Insurance.

Table 24. Nicardipine: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Emergency management of abnormal hypertension during surgery, hypertensive emergency Presence/absence of indications Approved Off-label Half-life T1/2 53~60 min Unknown Dosage 0.5~6 μg/kg/min 1~3 μg/kg/min Dosing method Continuous intravenous infusion Major adverse reactions - Palpitations, headache, facial hot flashes, edema, gingival hyperplasia, constipation - Serious adverse reactions include paralytic ileus, hypoxemia, pulmonary edema, and dyspnea. Characteristic features in children - In Europe and U.S., this drug is regarded as effective in preterm infants and neonates as well.

31–34 infants more than 6 months after birth and young or older IV. Arrhythmia (Tables 18 and 19) children: 50~100 mg/m2/day, at 2~3 divided doses per day, (increase and decrease); infants less than 6 months after birth: Antiarrhythmic drugs approved for pediatric use are flecainide 50 mg/m2/day, at 2~3 divided doses per day, (increase and (Ic) and the β-blocker propranolol, and the calcium channel decrease); and at a maximum daily dose: 200 mg in each case. blocker verapamil (IV). Mexiletine, pilsicainide, atenolol, and Although the dose of the calcium channel blocker verapamil landiolol are covered by the NHI (Table 18). (Vasolan) is set at 3~6 mg/kg/day, caution is necessary for use in In particular, the dosage of flecainide (Tambocor) has been conditions such as cardiac dysfunction, postoperative arrhythmia, indicated as the following: minutely as 4 mg/kg/day (Table 19); because the drug tends to be more potent in children (Table 20).

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Table 25. Antihypotensive Drugs Mechanism of Action - Elevating effect of systemic blood pressure by contraction of vascular smooth muscle Target diseases - Essential hypotension, orthostatic hypotension Drug type (or class) - α receptor agonists: phenylephrine hydrochloride, midodrine hydrochloride, ergotamine mesilate - Sympathetic stimulant: amezinium metilsulfate - Drugs approved for use in children and youth in Japan: midodrine hydrochloride Precautions for pregnant women and fetuses - Because ergotamine mesilate has uterotonic activity and placental and umbilical vasoconstrictor action, it is contraindicated for pregnant or breast-feeding women.

Table 26. Antihypotensive Drugs: Comparison of Adults and Children/Youth Adults Children/Youth [Midodrine hydrochloride] Target diseases Essential hypotension, orthostatic hypotension Presence/absence of indications Approved Half-life T1/2 2.4 hours Dosage 4~8 mg/day 4 mg/day according to age (maximum 6 mg/day) Dosing method 2 divided oral doses per day Major adverse reactions Headache, nausea, abdominal pain, vertigo, palpitations, ventricular arrhythmias. Contraindicated for hyperthyroidism and pheochromocytoma.

[Amezinium metilsulfate] Target diseases Essential hypotension, orthostatic hypotension Presence/absence of indications Approved Off-label Half-life T1/2 13.6±2.5 hours Unknown Dosage 20 mg/day 5~20 mg/day according to age Dosing method 2 divided oral doses per day Major adverse reactions Palpitations, headache, nausea/vomiting, facial hot flashes, hypertension. Contraindicated for hyperthyroidism and pheochromocytoma.

Table 27. Therapeutic Drugs for Pulmonary Arterial Hypertension Mechanism of action - Pulmonary vasodilation by relaxation of vascular smooth muscle cells Target diseases - Pulmonary arterial hypertension Drug type - Prostacyclins: beraprost (oral), epoprostenol (intravenous) - PDE5 inhibitors: sildenafil (Sil), tadalafil - Endothelin receptor antagonists: bosentan (Bos), ambrisentan (Amb) - Drugs approved for use in children and youth in Japan: None. Precautions for pregnant women and fetuses - Contraindications: teratogenesis found in animal experiments (Bos, Amb) - Caution: decreased blood flow in the uterus (Sil) PDE, phosphodiesterase.

35–38 Nifedipine is indicated for essential hypertension and renal V. Hypertension hypertension, Perdipine injection for emergency treatment of abnormal hypertension during surgery and hypertensive emer- Calcium channel blockers bind selectively to the voltage-de- gency, and amlodipine for hypertension (Table 21). pendent calcium channels and block them, and thereby cause Among these drugs, amlodipine is the only calcium channel a reduction in the flow of calcium ions into the cells, resulting blocker approved for use in children and youth. in a relaxation of the smooth muscle of coronary or peripheral Table 22 shows a comparison of the use of amlodipine in vessels, thus exerting antihypertensive and antianginal effects. adults and children/youth. In children, the dose should not ex-

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Table 28. PDE5 Inhibitor Sildenafil: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Pulmonary arterial hypertension (PAH) Presence/absence of indications Approved Off-label Half-life T1/2 3 hours Dosage 3 tablets (60 mg)/day 1~4 mg/kg/day Dosing method 3 divided doses per day 3~4 divided doses per day Major adverse reactions Facial hot flash, headache, erection (even in children), abnormal vision Characteristic features in children - Although a number of reports indicate high usefulness of this drug in pediatric PAH, its safety has not been established. - There are no data on the neonatal period, when vision is not yet stable. PDE, phosphodiesterase.

Table 29. Endothelin Receptor Antagonist Bosentan: Comparison of Adults and Children/Youth Adults Children/Youth Target diseases Pulmonary arterial hypertension (WHO-FC III/IV) Presence/absence of indications Approved Off-label Half-life T1/2 5 hours Dosage* Body weight ≥40 kg: 4~8 mg/kg/day (body weight <30 kg) 4 tablets (250 mg/day) Body weight <40 kg: 2 tablets (125 mg)/day (*Initial dose: starting at a 1/2 dose for 4 weeks) Dosing method 2 divided doses per day Major adverse reactions Headache, hepatic dysfunction, myalgia Characteristic features in children - A number of reports indicate high usefulness in pediatric pulmonary arterial hypertension. - Efficacy and safety have not been established. - Hepatic dysfunction is less frequent than in adults. WHO-FC: World Health Organization functional class.

Table 30. Therapeutic Drugs for Myocardial Diseases (Systolic dysfunction) Mechanism of Action: - Afterload reduction, preload reduction, myocardial protection Target diseases: - Dilated cardiomyopathy, noncompaction of ventricular myocardium, arrhythmogenic right ventricular cardiomyopathy Drug type (or class) 1. Cardiotonics: e.g., digitalis, digoxin 2. Diuretics: furosemide, spironolactone*, tolvaptan 3. Angiotensin-converting enzyme inhibitors: enalapril*, lisinopril 4. Angiotensin II receptor antagonists: candesartan, valsartan 5. β-blockers: carvedilol*, bisoprolol, metoprolol 6. Anti-aldosterone drugs: spironolactone* 7. Peripheral vasodilators: amlodipine, felodipine, milrinone*, olprinone* 8. Oral cardiotonics: pimobendan, denopamine*, docarpamine, vesnarinone Drugs approved for use in children and the youth in Japan: digoxin Drugs with an asterisk (*) are covered by the National Health Insurance. ceed the adult dose (overseas package inserts describe that there adults and children/youth. Nifedipine sustained-release tablets has been no study that examined doses exceeding 5 mg/day in should be used without changing the formulation. children). Table 24 shows a comparison of the use of nicardipine in *However, the present guideline documents also refer to the adults and children/youth. dosage “0.06~0.3 mg/kg/day, at one dose” as described in the 2009 guidelines of the European Society of Hypertension.36 Table 23 shows a comparison of the use of nifedipine in

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Table 31. Therapeutic Drugs for Myocardial Diseases (Diatolic dysfunction) Mechanism of Action: - Inhibition of myocardial contractility and excitability Target diseases: - Hypertrophic cardiomyopathy (obstructive/non-obstructive) Drug type (or class) 1. β-blockers: propranolol**, bisoprolol, metoprolol 2. Calcium channel blockers: verapamil**, diltiazem (caution required for hypertrophic obstructive cardiomyopathy) 3. Antiarrhythmic drugs: flecainide**, disopyramide*, cibenzoline, amiodarone The drug with an asterisk (*) is covered by National Health Insurance. Drugs with a double-asterisk (**) are approved for use in pediatric arrhythmias in Japan.

Table 32. Therapeutic Drugs for Cardiomyopathy Complicated by Specific Diseases Mechanism of Action - Enzyme replacement therapy for inborn errors of metabolism Target diseases (Indications for these orphan drugs are already approved based on limited pediatric data) 1. Fabry’s disease 2. Pompe’s disease Drug type 1. α-galactosidase preparations Agalsidase alfa: a dose of 0.2 mg/kg is given by intravenous drip infusion every other week Agalsidase beta: a dose of 1 mg/kg is given by intravenous drip infusion every other week 2. Acid α-glucosidase preparations Alglulcosidase alpha: a dose of 20 mg/kg is given by intravenous drip infusion every other week

Table 33. Therapeutic Drugs for Infective Endocarditis Mechanism of Action - Antibacterial drugs, antifungal drugs Target diseases - Diseases that have risk for infective endocarditis (mainly congenital heart disease) Drug type (or class) - β-lactamase inhibitors: benzylpenicillin (PCG), ampicillin sodium (ABPC) - First-generation cephems: cefazolin sodium (CEZ) - Third-generation cephems: ceftriaxone sodium (CTRX) - Glycopeptides: vancomycin hydrochloride (VCM) - Aminoglycosides: gentamicin sulfate (GM) - Antifungal drugs: amphotericin B (AMPH-B) Approved for use in children and youth in Japan: above all Precautions for pregnant women and fetuses: safety of administration during pregnancy has not been established. - Large-dose (3,000 mg/kg/day) administration of ampicillin sodium (ABPC) caused teratogenesis in rats. - GM: 8th cranial nerve disorder may occur in neonates.

40 agonists (phenylephrine hydrochloride, midodrine hydrochlo- VI. Hypotension (Table 25) ride, and ergotamine mesilate), and 2) sympathetic stimulants (amezinium metillsulfate). Orthostatic hypotension associated with orthostatic dysregula- Because of its uterotonic activity and placental and umbili- tion is common in childhood. Midodrine hydrochloride is the cal vasoconstrictor action, Dihydergot is contraindicated for only antihypotensive drug approved for pediatric use. Table 26 pregnant and breast-feeding women. shows a comparison of the use of midodrine hydrochloride Use of phenylephrine hydrochloride in children is off-label. (Metligine) in adults and children/youth. In adults, a dose of 2~5 mg is given by repeated subcutaneous The mechanism of action of antihypotensive drugs is blood injection, or 0.5~1.0 mg is diluted and given intravenously. In pressure elevation by contraction of vascular smooth muscle. children, this drug is administered by continuous infusion at a These drugs are indicated for essential hypotension and ortho- rate of 0.1~2.0 μg/min. Major adverse reactions include head- static hypotension. This type of drugs includes 1) α receptor ache, numbness in limbs, erythema, and cardiac palpitation.

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Table 34. Therapeutic Drugs for Infective Endocarditis Approval for Route, dose, method of Half-life in Characteristic Generic name Adverse reactions pediatric use administration blood features in children Benzylpenicillin Approved Intravenous: 3 hours (renal) Fever, rash, urticaria, (PCG) 200,000~300,000 U/kg/day, convulsions, skin lesions 4~6 divided doses per day Ampicillin sodium Approved Intravenous: 1 hour (renal) Fever, rash, urticaria, (ABPC) 200~300 mg/kg/day, convulsions, skin lesions 4 divided doses per day Cefazolin sodium Approved Intravenous: 2.3 hours (renal) Hypersensitivity, (CEZ) 100 mg/kg/day, thrombocytopenia, 4 divided doses per day hepatic dysfunction, gastrointestinal symptoms Ceftriaxone sodium Approved Intravenous: 4.7 hours (renal) Do not use in Hypersensitivity, (CTRX) (only for sepsis) 75~100 mg/kg/day, neonates and eosinophilia, 2 divided doses per day premature vitamin deficiencies, babies with gastrointestinal symptoms hyperbilirubinemia Vancomycin Approved Intravenous: 5.23 hours (renal) Shock, acute renal failure, hydrochloride 30~40 mg/kg/day, pancytopenia, mucocutaneous (VCM) 2~4 divided doses per day ocular syndrome, 8th cranial nerve disorder, pseudomembranous colitis Gentamicin sulfate Approved Intravenous: 3.27 hours (renal) Renal dysfunction, hepatic (GM) (only for sepsis) 3 mg/kg/day, dysfunction, eosinophilia 3 divided doses per day Amphotericin B Approved Intravenous drip infusion: Initial plasma half-life: Increased creatinine, (AMPH-B) 3.0~5.0 mg/kg/day about 24 hours, nausea, vomiting, elevation elimination half-life: of GOT and GPT, headache, about 15 days fever, rash, hypokalemia GOT, glutamic oxaloacetic transaminase; GPT, glutamate pyruvate transaminase.

Table 35. Prophylactic Drugs for Infective Endocarditis (All Unapproved for Pediatric Use) Route, dose, Generic name Half-life in blood Adverse reactions method of administration Amoxicillin (AMPC) Oral: 50 mg/kg (upper limit 2 g), 1 hour (renal) Gastrointestinal symptoms given 1 hour prior to procedure Ampicillin (ABPC) Intravenous injection: 50 mg/kg 1 hour (renal) Fever, rash, urticaria, convulsions, skin lesions (upper limit 2 g), given within 30 min of procedure Clindamycin phosphate Oral: 20 mg/kg (upper limit 600 mg), 2~3 hours (hepatic) Rash, neurological symptoms, hepatic damage, (CLDM) given 1 hour prior to procedure renal dysfunction, pancytopenia Cefalexin (CEX) Oral: 50 mg/kg (upper limit 2 g), 1.24 hours (renal) Fever, rash, urticaria given 1 hour prior to procedure Cefadroxil (CDX) Oral: 50 mg/kg (upper limit 3 g), NA Rash, hepatic damage, gastrointestinal symptoms, given 1 hour prior to procedure pancytopenia, vitamin deficiencies Azithromycin (AZM) Oral: 15 mg/kg (upper limit 500 mg), 66.2 hours Photosensitivity, eosinophilia, decreased blood given 1 hour prior to procedure pressure, fainting, convulsions, gastrointestinal symptoms, hearing difficulty, tinnitus Clarithromycin (CAM) Oral: 15 mg/kg (upper limit 500 mg), 4.36 hours Rash, gastrointestinal symptoms, eosinophilia, given 1 hour prior to procedure elevation of GOT Cefazolin sodium (CEZ) Intravenous injection: 50 mg/kg 2.3 hours (renal) Hypersensitivity, thrombocytopenia, hepatic (upper limit 1 g), given within dysfunction, gastrointestinal symptoms 30 min of procedure Ceftriaxone sodium Intravenous injection: 50 mg/kg 4.7 hours (renal) Hypersensitivity, eosinophilia, vitamin deficiencies, (CTRX) (upper limit 2 g), given within gastrointestinal symptoms 30 min of procedure Do not use in neonates and premature babies with hyperbilirubinemia. GOT, glutamic oxaloacetic transaminase; NA, not available.

hibitors, and endothelin receptor antagonists are used in chil- VII. Pulmonary Arterial Hypertension dren, but all these are off-label for pediatric use. 41–43 (Tables 27~29) Tables 28 and 29 show a comparison of the use of PDE5 inhibitor, and endothelin receptor antagonist bosentan, respec- The same as in adults, major drugs of prostacyclin, PDE5 in- tively, in adults and children/youth.

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Table 36. Treatment of Patent Ductus Arteriosus (PDA) in Premature Newborns Pharmacological treatment with COX inhibitors (e.g., indomethacin, ibuprofen) is effective. Medications are given prior to surgical ligation. - Pharmacological closure using COX inhibitors: The mainstay of therapy is intravenous indomethacin. This treatment is approved for PDA in premature newborns in Japan. - Dose and dosing intervals: A dose of 0.1~0.2 mg/kg is given every 12~24 hours. Intravenous administration of up to 3 serial doses is recommended. - Adverse reactions: Oliguria, renal failure (occasionally), hypoglycemia, bleeding tendency, gastrointestinal bleeding, gastrointestinal perforation (occasionally), NEC, increased unbound bilirubin - Prophylactic administration: A significant reduction is achieved in the incidence of symptomatic PDA, rate of ductus arteriosus ligation, and frequency of severe IVH in acute phase (degree III and IV of IVH), demonstrating effectiveness in improving short- term prognosis. It is recommended to perform continuous intravenous infusion of 0.1 mg/kg per dose over a 6-hour period within 6 hours after birth. - Concerning ligation: Surgery is indicated primarily for patients who do not respond to COX inhibitors and those in whom COX inhibitors are contraindicated. COX, cyclooxygenase; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis.

Table 37. Comparison of NO Inhalation Therapy, Vasodilators, and ECMO Therapy Advantages Disadvantages NO inhalation therapy - Selectively dilates pulmonary blood - Adverse reactions to NO inhalation INOvent + INOflo vessels therapy - No effects on systemic blood pressure Methemoglobinemia Increase in inspired NO2 concentration - Minimally invasive - No limitations in the body weight - Readily connecTable to the ventilator circuit Medical products - Intravenous administration (no special - No selectivity to pulmonary circulation Vasodilators (epoprostenol, device necessary) - Decreased blood pressure due to prostaglandin) systemic vasodilation Medical devices - The only life-saving rescue treatment - High invasiveness ECMO therapy - Stress injury associated with artificial - Risk from heparin use ventilation can be avoided - Limited indication: body weight <2 kg, vascular diameter incompatible to cannula diameter - High manpower and labor: required for circuit assembly, maintenance, and replacement ECMO, extracorporeal membrane oxygenation; NO, nitric oxide.

Table 38. Pharmacologic Agents for Stress Test in Radionuclide Imaging Mechanism of Action - Coronary vasodilator-derived imbalance of coronary flow in the ischemic region. Dobutamine provides substi- tuted exercise stress by increasing myocardial oxygen demand. Target diseases - Ischemic heart diseases including Kawasaki disease: adenosine, adenosine triphosphate, dipyridamole, dobutamine Drugs approved for use in children and youth in Japan - None

14,44,45 2. Dilation Management (Table 31) VIII. Myocardial Diseases (Table 30) Hypertrophic cardiomyopathy is the representative disease.

1. Contractile Impairment 3. Cardiomyopathy Complicated by Specific Diseases Dilated cardiomyopathy is the representative disease. See also (Table 32) the section on heart failure as needed. This group of cardiomyopathies is chiefly associated with in-

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Table 39. Immunosuppressive Drugs: Calcineurin Inhibitors Mechanism of Action - Inhibition of transcription of IL2 and other factors, through inhibition of calcineurin dephosphorylated enzyme in T lymphocytes Target diseases - For immunological suppression of rejection response after organ transplantation Drug type - Cyclosporine: Neoral (oral), Sandimmune (oral capsule, oral solution, and drip infusion) Pediatric kidney transplantation: Neoral 3~6 mg/kg in 2 divided doses (target trough level: 80~100 ng/mL) - Tacrolimus: Prograf (oral, intravenous) Pediatric kidney transplantation: Prograf 0.2~0.4 mg/kg in 2 divided doses (target trough level: 4~5 ng/mL) Drugs approved for use in children and youth in Japan - Approved for transplantation of the kidney, liver, heart, lung, pancreas, small intestine, and bone marrow (small intestine is not referred to for Sandimmune Capsule) Precautions for use - Blood concentration should be adjusted carefully according to the timing of transplantation, rejection response, and presence/absence of infection - There are interactions with many drugs through induction or inhibition of CYP3A4/5 metabolism CYP, cytochrome; IL, interleukin.

Table 40. Inhalational Anesthetic Drugs Mechanism of Action - Mechanism of action of general anesthesia with inhalational anesthetic drugs has not been elucidated. Indications - Induction and maintenance of anesthesia - Status asthmaticus (sevoflurane, isoflurane) Drug type (or class) - Volatile anestheic drugs: sevoflurane, isoflurane - Gas anesthetics: nitrous oxide (“laughing gas”) Drugs approved for use in children and youth in Japan - Sevoflurane, nitrous oxide, isoflurane Precautions for pregnant women and fetuses - Sevoflurane and isoflurane have a relaxing action of the uterus. - Nitrous oxide may increase the rate of spontaneous abortion.

born errors of metabolism, and mainly treated by enzyme re- initial inhalation concentration at 20 ppm, and maintained at placement therapy. 20 ppm for subsequent 4 hours. When improved oxygenation is achieved, the dose is decreased to 5 ppm, and therapy should 46–48 be discontinued after the dose is decreased gradually to 1 ppm. IX. Infective Endocarditis (Table 33) Extracorporeal membrane oxygenation (ECMO) is indicated for severe cases that do not respond to therapy. Various antibacterial drugs are available. Tables 34 and 35 show therapeutic drugs and prophylactic drugs, respectively, 53–55 for bacterial endocarditis. XI. Radionuclide Imaging (Table 38)

Isotope-labeled preparations are used for myocardial imagings X. Premature and Newborn in cases of ischemic heart disease (e.g., Kawasaki disease, 49–52 Medicine (Table 36) coronary artery anomaly), cardiomyopathy, and myocarditis. These drugs include technetium-99 m-tetrofosmin, techne- Intravenous indomethacin is used to assist in ductus arteriosus tium-99 m-MIBI (methoxy-isobutyl isonitrile), and thallium- closure. In cases of patent ductus arteriosus depending con- 201-chloride for myocardial perfusion imaging; I-123 BMIPP genital heart disease, continuous intravenous infusion of pros- (β-methyl-p-123I-iodophenyl-pentadecanoic acid) for myo- taglandin E1-CD (Prostaglandin Injection® 50~150 ng/kg/min) cardial fatty acid metabolism imaging; and I-123 MIBG or a lipoidal form of this agent (Palux® or Liple® Injection (m-I123-iodobenzylguanidine) for cardiac sympathetic nerve 5~10 ng/kg/min) is used. imaging. All these drugs are approved for use in children and In cases of persistent pulmonary hypertension of newborns youth in Japan. No pharmacologic stress agent has been ap- (Table 37), INOflo® (for inhalation 800 ppm), an inhalation proved for use in children. nitric oxide (NO) drug, is used. Therapy is started with the

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Table 41. Inhalational Anesthetic Drugs (Sevoflurane, Isoflurane, Nitrous Oxide): Comparison Between Adults and Children/Youth Adults Children/Youth Target conditions Induction and maintenance of anesthesia, status asthmaticus (only for sevoflurane and isoflurane) Presence/absence of Approved indications Dosage Sevoflurane: 5.0~8.0% for induction of anesthesia. Anesthesia should be maintained at minimum effective concentration usually in combination with other anesthetic drugs. Isoflurane: Up to 4.0% for induction of anesthesia. Anesthesia should be maintained at minimum effective concentration usually in combination with other anesthetic drugs. Nitrous oxide: Used with 30% or higher concentration of oxygen for induction of anesthesia. Anesthesia is maintained at 50~70% nitrous oxide, basically in combination with other inhalational anesthetic drugs. Major adverse reactions Sevoflurane, isoflurane: malignant hyperthemia, cardiorespiratory depression, rhabdomyolysis, anaphylactic symptoms, uterine relaxation Nitrous oxide: peripheral neuropathy, disturbance of hematopoiesis, internal closed cavity pressure elevation, diffusion hypoxemia, combustion aid, possibility to increase the rate of spontaneous abortion Characteristic features in Sevoflurane: MAC in children differs from that in adults and is as follows: 3.3% for children and precautions 0~1-month-old term infants, 3% for infants 2~6 months after birth, 2.8% for infants 7 months for use to less than 3 years after birth, and 2.5% for children aged 3~12 years. If there is a history of convulsion, there is a risk of convulsive attacks being induced. SuiTable for induction of anesthesia by inhalation because airway irritation is minimal. Isoflurane: MAC in children differs from that in adults and is as follows: 1.6% for 0~1-month-old term infants, 1.87% for infants 2~6 months after birth, 1.8% for infants 7~12 months after birth, and 1.6% for infants 1~5 years after birth. Because this drug causes mild airway irritation, it is not suiTable for induction of anesthesia by inhalation (no indication for neonates, infants, or young children). MAC, minimum alveolar concentration.

Table 42. Analgesics (Morphine, Fentanyl): Comparison Between Adults and Children/ Youth Adults Children/Youth Target conditions Pain during anesthesia, postoperative, and other conditions Presence/absence of indications Approved Half-life T1/2 About 3.6 hours (fentanyl) Shorter than in adults (fentanyl) Dosage (Fentanyl) - 2~6 μg/kg at induction of anesthesia, with addi- - Slow intravenous infusion of 1~5 μg/kg at induction tional doses of 25~50 μg/kg or continuous adminis- of anesthesia. For high-dose fentanyl anesthesia, tration at 0.5~5 μg/kg/h (50~100 μg /kg may be usually up to 100 μg/kg can be used. used during anesthesia for cardiac surgery). - Intermittent intravenous infusion of 1~5 μg/kg for - For postoperative pain, initial dose (1~2 μg/kg) is maintenance of anesthesia. given intravenously, and followed by continuous - For postoperative pain, slow intravenous infusion intravenous infusion at 1~2 μg/kg/h. of 1~2 μg/kg is used, and followed by drip infusion - For patient controlled analgesia given by continu- at 1~2 μg/kg/h. ous administration at 4~60 μg/h, with single doses of 7~50 μg at intervals of 5~10 minutes according to the severity of pain. (Morphine) - 0.1~0.4 mg/kg is given for anesthetic purposes. - 0.01~0.03 mg/kg is usually given intravenously for - For postoperative analgesia and sedation, the anesthetic purposes. drug is given at 0.1~0.2 mg/kg every 4~6 hours, - For postoperative pain, single intravenous dose of or given continuously at 10~60 μg/kg/h. 0.05~0.2 mg/kg for children or 0.05 mg/kg for infants, or continuous intravenous dose of 10~40 μg/kg/h (usually 20 μg/kg/h) for children or 5~15 μg/kg/h for infants is used. Major adverse reactions Contraindicated for patients in convulsive state and during bronchial asthma attacks. Physical dependency, respiratory depression, bradycardia, hypotension, nausea/vomiting, constipation, urinary retention, itching, muscle stiffness, shivering (all for morphine and fentanyl), histamine release (morphine), and increased biliary tract pressure (morphine). Contraindicated for patients with hemorrhagic colitis (morphine). Characteristic features in - Children are easy to develop respiratory depression, and thus adequate monitoring is necessary. children and precautions for use - Muscle stiffness at induction of anesthesia may cause ventilation difficulty, and therefore is dangerous in children who have less physical reserve. In such cases, muscle relaxants are effective.

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Table 43. Analgesic (Remifentanil): Comparison Between Adults and Children/Youth Adults Children/Youth Target conditions Pain relief during anesthesia Presence/absence of indications Approved Off-label Half-life T1/2 About 8~20 minutes Same as adults in any age group Dosage - Continuous intravenous infusion at a rate of - It is desirable to avoid single administration 0.5 μg/kg/min for induction of anesthesia. because it may cause extreme bradycardia. 2.0 μg/kg/min or a lower rate during maintenance - Continuous intravenous infusion starting at a rate of anesthesia. of 0.25~0.5 μg/kg/min, and the dose is adjusted - For single intravenous administration, 1.0 μg/kg is according to the patient’s vital signs and surgical given over 30~60 seconds. stress. Major adverse reactions Physical dependency, respiratory depression, bradycardia, hypotension, nausea/vomiting, constipation, urinary retention, itching, muscle stiffness, and shivering Characteristic features in - Children are easy to develop respiratory depression, and thus adequate monitoring is necessary. children and precautions for use - Muscle stiffness at induction of anesthesia may cause ventilation difficulty, and therefore is dangerous in children who have less physical reserve. In such cases, muscle relaxants are effective.

Table 44. Intravenous Anesthetics (Ketamine, Barbiturates): Comparison Between Adults and Children/Youth Adults Children/Youth Target conditions - Induction and maintenance of anesthesia - Premedication, analgesic support during general anesthesia, sedation during procedure and testing, postoperative pain control and sedation (ketamine) - Convulsion (barbiturates) Presence/absence of indications Approved Half-life T1/2 107.3 minutes (ketamine) 184.7 minutes in infants 3 months old or younger, 6~12 hours (barbiturates) 65.1 minutes in infants 4~12 months after birth, 31.6 minutes (ketamine) and about 6.1 hours (barbiturates) in children at age 4 years Dosage (Ketamine) - Initial intramuscular dose is 5~10 mg/kg. - Initial intramuscular dose is 4~8 mg/kg. For intra- - For intravenous administration, initial intravenous venous administration, initial intravenous dose is dose is 1~2 mg/kg, and the same dose or half 1~2 mg/kg, and the same dose or half dose is dose is added. added. - For analgesic support during general anesthesia, 0.25~0.5 mg/kg is given intravenously, with additional half doses given every 30 minutes or continuous infusion of 0.25~0.5 mg/kg/h. - For premedication, 5~6 mg/kg is given orally, or 5~10 mg/kg rectally. (Barbiturates) - For induction of anesthesia, 3~5 mg/kg is given - For induction of anesthesia, intravenous thiopental intravenously. Short-term general anesthesia is at 5~6 mg/kg is given in healthy children 1 year old induced with a dose of 3~4 mg/kg, and 10~100 mg or older. 7~8 mg/kg may be necessary in infants. is added according to the patient’s condition. - In patients with status epilepticus, 5 mg/kg is given - In patients with status epilepticus, 5~7 mg/kg is intravenously, and additional continuous infusion given intravenously, and 50 mg bolus doses or may be started at a rate of 2 mg/kg/h if needed. continuous infusion of 3~5 mg/kg/h is added until The dose may be increased gradually to burst suppression is obtained. 10 mg/kg/h until disappearance of status epilepticus is confirmed on electroencephalogram. Major adverse reactions (Ketamine) Cerebrovascular disorder, hypertension, increased intracranial pressure, convulsion (e.g., laryngospasm, glottis spasm, or generalized convulsion), increase in airway secretion, respiratory depression, and responses in the waking state including hallucination, excitation, and confusion (Barbiturates) - Contraindicated for patients with acute intermittent porphyria, those with Addison’s disease, and those with severe bronchial asthma. - Hypotension, respiratory depression, and local irritation or necrosis due to extravasation. Characteristic features in - There is large difference among individual infants in the dose of thiopental necessary for induction of children and precautions for use general anesthesia (barbiturates). - In principle, a period of NPO from food and drink is required prior to administration (barbiturates). NPO: nothing per OS.

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Table 45. Intravenous Anesthetic Drug (Propofol): Comparison Between Adults and Children/Youth Adults Children/Youth Target diseases Induction and maintenance of anesthesia Sedation during artificial ventilation in intensive care (in adults only) Presence/absence of indications Approved Unapproved (maintenance and induction of anesthesia) Half-life T1/2 About 240 minutes 209 minutes (age 4~12 years) Dosage - 1.0~2.5 mg/kg for induction of anesthesia, and - Although induction of anesthesia at 2~4 mg/kg continuous administration of 4~10 mg/kg/h for achieves deep sedation, the dose required for deep maintenance. sedation generally increases in children of earlier - When Diprifusor TCI (target controlled infusion) age (infants: 3.8 mg/kg, age 10~16 years: 2.7 mg/kg). function is used, administration may be started at - For induction of anesthesia in children aged 3~11 a target blood concentration of 3 μg/mL. The dose years, a concentration of 3 μg/mL will provide deep is adjusted by 1~2 μg/mL at a time, and anesthesia sedation and can be achieved over time by the follow- is maintained at 2~5 μg/mL. ing procedures: 2.5 mg/kg bolus, followed by admin- - For sedation in intensive care, continuous administration of 15 mg/kg/h over 15 minutes, 13 mg/kg/h istration of 0.3~3 mg/kg/h is given. over the subsequent 15 minutes, 11 mg/kg/h over the subsequent 30 minutes, 10 mg/kg/h over 1 hour between 1 and 2 hours after the bolus, and 9 mg/kg/h between 2 and 4 hours after the bolus. Major adverse reactions - Contraindicated for long-term large-dose administration in pregnant women, children, and patients who have a history of hypersensitivity to the ingredients of this drug (soybean oil, egg-yolk lecithin). - Anaphylaxis, hypotension, respiratory depression, glossoptosis, severe bradycardia, bradyarrhythmia, and the possibility of increased blood lipid concentration in patients with lipid metabolism disorder Characteristic features in - A period of NPO from food and drink is required prior to administration. children and precautions for use - Careful judgment including the propriety of administration is required in premature infants or term newborns within 1 week of life because they have a low propofol clearance and are presumably likely to have accumulation of propofol after repeated administration or continuous intravenous infusion. - In children under general anesthesia, particular attention should be paid to “propofol infusion syndrome” including metabolic acidosis, rhabdomyolysis, and heart failure complicated with hyperkalemia predis- posed by long-term, high-dose propofol therapy. - In children, propofol is “contraindicated” for use aimed at sedation during artificial ventilation. - In children, the same TCI function as in adults cannot be used because pharmacokinetics differ between children and adults. NPO: nothing per OS.

A comparison of inhalation anesthetic drugs for adults and XII. Immunosuppressive for Organ children is shown in Table 41. Transplantation (Table 39)56–60 2. Analgesics Cyclosporine (Sandimmune, Neoral) and tacrolimus are ap- Analgesics are indicated for pain during anesthesia (morphine, proved for use in the transplantation of kidney, liver, heart, fentanyl, remifentanil), postoperative pain and other severe lung, pancreas, small intestine, and bone marrow (small intes- pain (morphine, fentanyl). The types of drugs used include tine is not referred to for Sandimmun Capsule). The safety of fentanyl and morphine (Table 42) and remifentanil (Table 43). these drugs has been established in low-birth-weight new- Analgesics approved for use in children and youth in Japan are borns, neonates, and infants. Patients with appropriate indica- fentanyl and morphine. tions should be selected carefully and observed sufficiently. Cyclosporine and tacrolimus preparations are approved for 3. Intravenous Anesthetic Drugs use in all patients after organ transplantation excluding small Intravenous anesthetic drugs are indicated for induction and intestine transplantation. In addition, CellCept 25~50 mg/kg/day maintenance of anesthesia, premedication, analgesic adjuvant and Bredinin 3~6 mg/kg/day, administered by 1 or 2 divided during general anesthesia, sedation at the time of treatment and doses, are used. The recommended therapeutic doses for renal examination, postoperative pain relief and sedation (ketamine), transplantation in children are as follows: Neoral 3~6 mg/kg anticonvulsant medication (barbiturates), and sedation in arti- in 2 divided doses (target trough 80~100 ng/mL), Prograf ficial respiration during intensive care (propofol). The types of 0.2~0.4 mg/kg in 2 divided doses (target trough 4~5 ng/mL), drugs used include ketamine, barbiturates (thiopental, thiamylal) CellCept 600~1,200 mg/m2 in 2 divided doses, Bredinin (Table 44), and propofol (Table 45). Among these, ketamine and 3~6 mg/kg in 1or 2 divided doses. barbiturates are approved for use in children and youth in Japan.

61–66 4. Sedatives XIII. Anesthetic and Sedatives Sedatives are used for sedation in intensive care units, testing, treatment, anesthetic premedication, and in the induction and 1. Inhalational Anesthetic Drugs maintenance of anesthesia (midazolam). The drugs used include Inhalation anesthetic drugs approved for pediatric use are sevo- midazolam and dexmedetomidine. Midazolam is approved for flurane, isoflurane, and nitrous oxide (See Table 40). use in children and youth in Japan (Table 46).

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Table 46. Sedatives (Midazolam): Comparison Between Adults and Children/Youth Adults Children/Youth Target conditions Premedication, induction, and maintenance of anesthesia; sedation during artificial ventilation in intensive care unit Sedation during artificial ventilation in intensive care (adults only) Presence/absence of indications Approved Half-life T1/2 1.8~6.4 hours (after a single intravenous dose) Longer in premature newborns and neonates, and similar or shorter in children aged 1~12 years, compared to adults. Dosage Anesthetic premedication: 0.08~0.1 mg/kg, intramus- Anesthetic premedication: (excluding low-birth- cularly weight infants and neonates) 0.2~1.0 mg/kg, usually Induction of anesthesia: (excluding low-birth-weight 0.5 mg/kg (maximum dose 20 mg), given orally (chil- infants and neonates) 0.15~0.3 mg/kg intravenously, dren aged 1~6 years). 0.2~1.0 mg/kg (maximum with additional half or same doses as the initial dose 20 mg) by rectal administration (children aged 1~6 if necessary. years). 0.1~0.5 mg/kg, usually 0.1~0.15 mg/kg (maximum 10 mg), intramuscularly. 0.2~0.3 mg/kg Sedation in intensive care unit: Initial dose by nasal drip. 0.03~0.06 mg/kg, with additional doses if necessary. Induction of anesthesia: (excluding low-birth-weight Maintenance dose 0.03~0.18 mg/kg/h infants and neonates) 0.15 mg/kg intravenously, with additional half or same doses as the initial dose if necessary. Sedation in intensive care unit: (excluding low-birth- weight infants and neonates) Initial dose 0.05~0.2 mg/kg. Maintenance dose 1~2 μg/kg/min. Sedation in intensive care unit: (low-birth-weight infants and neonates) Administration may be started at a rate of 0.5 μg/kg/min for infants less than 32 weeks after birth or with 1 μg/kg/min for those at least 32 weeks after birth. Major adverse reactions Respiratory depression, hypoventilation, airway obstruction, circulatory depression, delirium, involuntary movements (e.g., clonic convulsion, muscular tremor, myoclonic seizure), hyperkinesia, drug resistance, withdrawal symptoms Characteristic features in children - Safety data about continuous intravenous infusion of midazolam for sedation of neonates in intensive and precautions for use care are insufficient, and there is no established evidence. - Rapid intravenous infusion should be avoided in low-birth-weight infants and neonates. - Airway obstruction and hypoventilation are particularly likely to occur in infants less than 6 month after birth.

Table 47. Muscle Relaxant (Rocuronium): Comparison Between Adults and Children/ Youth Adults Children/Youth Target conditions Muscle relaxation during general anesthesia and muscle relaxation during tracheal intubation Presence/absence of indications Approved Approved (careful administration in neonates, infants, and young children) Half-life T1/2 75 minutes Unkown* Dosage - Dose for intubation in adults: 0.6 mg/kg given - Dose for intubation 0.6~0.8 mg/kg intravenously, with additional doses of 0.1~0.2 mg/kg if necessary during surgery. - Continuous infusion: starting at a rate of 7 μg/kg/min. Major adverse reactions - Prolonged muscle relaxation, pain at the time of injection, rhabdomyolysis, shock, and anaphylactoid symptoms - Due caution is necessary for patients with neuromuscular disease because various responses may occur. Patients with myasthenia gravis and Eaton-Lambert syndrome have extremely high sensitivity. The duration of action varies greatly among different individuals. Characteristic features in - In children, onset and duration of action are short. children and precautions for use - The higher the dose for intubation, the longer the time required for recovery. Particularly in neonates and infants, the duration of action is longer than in children. Time to recovery is reported to be shorter in children aged 2 years or older than it is in adults. - Although not specific to this drug, there have been reports of hearing loss occurring in neonates and infants with severe illness who were on long-term therapy with other nondepolarizing muscle relaxants. - The use of a muscle relaxation monitor is recommended for adults. In neonates and infants, tetanic stim- ulation may induce attenuation even under normal conditions, and thus, the usefulness of the monitor in these patients is uncertain. *55.7 minutes in infants 3~12 months after birth, 49.9 minutes in children 1~3 years, 38.3 minutes in children 4~8 years.67

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5. Muscle Relaxants is indicated for use in neonates, infants, and young and older Muscle relaxants are used for muscle relaxation during gen- children) (Table 47). More details are available in “Guidelines eral anesthesia and tracheal intubation. There are three types for Use of Anesthetics and Anesthesia-Related Drugs, 3rd of muscle relaxants: rocuronium, vecuronium, and suxametho- revised edition (2012. 10. 31), Chapter X. Pediatric Anesthesia nium. Among these drugs, the one approved for use in chil- Drugs,” by the Japanese Society of Anesthesiologists.68 dren and youth in Japan is rocuronium (careful administration

Summary (Table 48)

As for medical products used in the field of pediatric cardio- cal evaluation of drugs of this kind worldwide, resulting in a vascular diseases, data from well-designed clinical studies lack of high-quality evidence in this field. Therefore, many have been limited. Instead, evidence is restricted to experts’ drugs that are indicated for adult diseases remain to be devel- opinions. Consideration for risk/benefit and informed consent oped for pediatric use. Table 49 shows a list of cardiovascular are important, and it is necessary to refer severe cases to insti- drugs used for children around the world.69 This list includes tutions where pediatric cardiologists are available. a number of globally recognized drugs, although some have Table 49 shows the doses of major drugs used for pediatric yet to be approved for pediatric use in Japan. This table has cardiovascular diseases described in a representative textbook been cited from Anderson’s basic textbook of pediatric cardi- (Anderson RH, et al. Pediatric Cardiology, third edition, 2009).69 ology. The dosing basically covers neonates to 10-year-old children. However, this table provides rough standards, and 69 the doses should be chosen appropriately by the doctor in I. List of Cardiovascular Drugs for Children charge who considers the risk/benefit based on the physical development, immaturity, race difference, renal and hepatic Conclusion function, dehydration status, presence/absence of fever, sever- Clinical studies of new drugs for pediatric use have been lim- ity of the disease, complications, and concomitant medications ited, and there have been few established guidelines for clini- in individual patients and other factors.

Table 48. Summary 1. Drugs that can be used clinically in children are limited. 2. Currently many drugs are lacking definitive evidence for safety. 3. However, usefulness has been reported frequently in guidelines of relevant academic societies, textbooks, and medical journals. 4. A number of drugs are already usable through application by medical and pharmaceutical public knowledge, and several drugs are covered by the National Health Insurance. 5. When the use of drugs that have not been examined in clinical studies is attempted, it is necessary to chose safe drugs that are less likely to affect the fetus, breast milk, and “growth and development” after the neonatal stage, based on consideration for the risk/benefit and characteristics of Japanese people. 6. It should be noted that adults and children may slightly differ in their therapeutic dose, pharmacokinetics, pharmacodynamics, and adverse reactions. Physicians should take great care when they prescribe drugs for children by simply converting the therapeutic dose for adults on the basis of body weight alone.

Table 49. Drugs Commonly Used for Cardiovascular Diseases in Children69 Drug Serious adverse General dosage and generic name Indications Contraindications Comments reactions dosing method [trade name]# Adenosine - Diagnosis of - AV block - Chest pain Rapid intravenous infusion of - ECG monitoring and record- [Adephos, ATP] arrhythmias - Bronchial asthma - Dyspnea 0.1 mg/kg per dose ing are necessary for rapid - Termination of - Bronchospasm Maximum dose intravenous infusion. supraventricu- - Severe brady- - Neonates: 0.3 mg/kg per - Gradual escalation of the lar arrhythmias cardia dose dose can be repeated every - Infants or older children: 2 minutes in rapid intrave- 0.5 m/kg per dose nous infusion until ECG changes occur. Alprostadil - Maintenance - Apnea - Drip infusion starting at a - Monitoring of heart rate, (prostaglandin E1) of patent - Tachypnea rate of 10 ng/kg/min breathing, and body temper- [Prostandin] ductus arterio- - Hypotension - The dose can be increased ature is necessary. sus in - Fever up to 50 ng/kg/min accord- - Artificial ventilation for neonates - Cortical prolifer- ing to response. apnea may be necessary. ation of long bones - Necrotizing enterocolitis

(Table 49 continued the next page.)

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Drug Serious adverse General dosage and generic name Indications Contraindications Comments reactions dosing method [trade name]# Amiloride - Potassium - Hyperkalemia - Hyponatremia - 200 μg/kg orally twice per - Diuretic effect will be [No approved drug sparing - Renal failure - Hyperkalemia day decreased by concomitant products in Japan] diuretic - Hypotension - Maximum daily dose 20 mg use with thiazide or loop diuretics. Amiodarone - Supraventricu- - Bradycardia - Bradycardia, [Oral] - To suppress development [Ankaron] lar arrhythmias - AV block torsades de - Initial dose: 5 mg/kg 2~3 of adverse reactions, long- - Ventricular - Hypotension pointes times per day for 7 days, term use should be avoided. arrhythmias - Thyroid disorder then decreased to mainte- - Careful monitoring of liver - Interstitial pneu- nance dose function, thyroid function, monia, pulmo- - Maintenance dose: 5 mg/kg interstitial pneumonia, nary fibrosis once per day, or adjustment aggravation of arrhythmias, - Alveolar hemor- based on measurement of bradycardia, and vision is rhage, ARDS blood concentrations necessary. - Hepatic dysfunc- [Intravenous] - Because photosensitivity tion, hepatitis - 25 μg/kg/min for the first and depigmentation of skin - Corneal pigmen- 4 hours, then decreased to are severe, sun block is tation 5~15 μg/kg/min necessary. - Photosensitivity, - Maximum daily dose 1.2 g - Monitor the heart rate depigmentation during intravenous infu- of skin sions, and adjust the dose if - Neurological necessary. disorder, anemia - Effective blood concentra- - SIADH tions of amiodarone and active metabolites: 0.6~2.5 mg/L Aspirin - Low dose: - Viral infection - Reye’s - Low dose: 5 mg/kg once per - High dose is aspirin is also [Aspirin] antiplatelet with the risk of syndrome day (maximum 75 mg) used in rheumatic fever and prophylaxis Reye’s syndrome - Hemorrhage - High dose: 20~25 mg/kg 4 post-pericardiotomy against throm- - Hemorrhagic (particularly time per day for approxi- syndrome. bosis gastric ulcer gastrointestinal mately 14 days, then - High dose: tract) decreased to the low dose anti-inflamma- - Bronchospasm tory agent for Kawasaki disease Atenolol - Hypertension - Bronchial asthma - Bradycardia - 1~2 mg/kg orally once per - Administration may be [Tenormin] - Supraventricu- - AV block - Heart failure day started at a low dose if there lar tachycardia - Hypotension - Bronchospasm - Maximum daily dose 100 mg is renal or hepatic dysfunc- - Ventricular - Cardiac dysfunc- - AV block tion. tachycardia tion - Peripheral vaso- constriction - Fatigue Captopril - Heart failure - Renal dysfunction - Hypotension - Starting at a rate of - ACE inhibitor [Captoril] - Hypertension - Renovascular (particularly with 0.1 mg/kg orally 3 times per - Usually used with loop disease initial doses) day diuretics for heart failure. - Coarctation of - Renal dysfunc- - The dose can be increased - Do not use with potassium the aorta tion up to 1 mg/kg orally 3 times sparing diuretics. - Left ventricular - Tachycardia per day. - Careful observation is outflow tract - Photosensitivity required at the initial induc- obstruction - Persistent dry tion. - Left ventricular cough - Usually, in an in-patient to inflow obstruction ensure monitoring of blood pressure and renal function. Carvedilol - Heart failure - Bronchial asthma - Bradycardia - Starting at a rate of - Used as a third-line therapy [Artist] - AV block - Heart failure 0.05 mg/kg orally twice per for chronic heart failure that - Cardiac dysfunc- - Bronchospasm day (maximum daily dose can be added after diuretics tion - AV block 3.125 mg) and ACE inhibitors - Periphreal vaso- - The dose can be increased - No evidence of long-term constriction every 2 weeks to a final usefulness in children has - Fatigue dose of 0.35 mg/kg orally been available. twice per day (maximum daily dose 25 mg) Clopidogrel - Antiplatelet - Hemorrahage - 1 mg/kg orally once per day - Used as a second-line [Plavix] prophylaxis - Thrombocytope- (maximum daily dose therapy after aspirin against throm- nia 75 mg) bosis as an alternative to low-dose aspirin

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Drug Serious adverse General dosage and generic name Indications Contraindications Comments reactions dosing method [trade name]# Digoxin - Supraventricu- - AV block - Anorexia [Oral] - In urgent circumstances, [Digosin] lar arrhythmias - Renal failure - Abdominal pain - Neonates to age less than 5 loading doses (digitaliza- - Heart failure - WPW syndrome - AV block years: 10 μg/kg/day, age tion) may be required over - Ventricular tachy- - Arrhythmias 5~10 years: 6 μg/kg/day the first 24 hours. cardia - Maximum daily dose 250 μg - The dose should be decreased in preterm neonates and children with renal failure. - Because of limited usefulness in heart failure, rarely used as first-line therapy. - Intravenous administration is rare. - Effective blood concentrations of digoxin are 0.8~2.0 μg/L. Dinoprostone - Patent ductus - Apnea - Drip infusion starting at a - Monitoring of heart rate, (Prostaglandin E2) arteriosus in - Tchypnea rate of 5 ng/kg/min breathing, and body temper- [Prostandin E2] neonates - Hypotension - The dose can be increased ature is necessary. - (In Japan, - Fever up to 20 ng/kg/min accord- - Artificial ventilation for uterine - Cortical prolifer- ing to response. apnea may be necessary. constriction) ation of long bones - Necrotizing enterocolitis Dipyridamole - Antiplatelet - Heart failure - Hypotension - 2.5 mg/kg orally twice per - Dipyridamole has also been [Anginal] prophylaxis - Aortic stenosis - Tachycardia day used for ischemic heart [Persantin] against throm- - Bronchospasm - Age 12 years or older: disease and steroid-resis- bosis as an 100~200 mg orally 3 times tant nephrosis. alternative to per day - The antiplatelet action may low-dose be synergistic with aspirin. aspirin Dobutamine - Inotropic - Left ventricular - Tachycardia - 2~20 μg/kg/min by continu- [Dobutrex] support in low outflow tract - Hypotension ous intravenous infusion cardiac output obstruction Dopamine - Hypotension - Tachycardia - Hypertension - 2~20 μg/kg/min by continu- - No evidence of effective [Inovan] - Low cardiac - Arrhythmia - Tachycardia ous intravenous infusion vasodilatory activity of low output - Arrhythmias doses dopamin in clinical settings. Enalapril - Heart failure - Renal failure - Hypotension - Starting at a rate of - ACE inhibitor [Renivace] - Hypertension - Renovascular (particularly with 0.1 mg/kg/day orally - Usually used with loop disease initial doses) - The dose can be increased diuretics for heart failure. - Coarctation of - Renal dysfunc- to 1 mg/kg/day according to - Do not use with potassium aorta tion response. sparing diuretics. - Left ventricular - Tachycardia - Careful observation is outflow tract - Raynaud’s required at the initial induc- obstruction symptoms tion. - Left ventricular - Stevens-Johnson - Usually, in an in-patient to inflow stenosis syndrome ensure monitoring of blood obstruction - Alopecia pressure and renal function. - Muscle cramp - Persistent dry cough Epinephrine - Acute hypo- - Hypertension - Tachycardia - 0.1 μg/kg/min intravenously (Adrenaline) tension - Hypertension - The dose can be increased [Bosmin] - Arrhythmias up to 1.5 μg/kg/min. Esmolol - Emergency - Bronchial asthma - Bradycardia - Initial dose: slow intrave- - Relatively cardioselective [Brevibloc] management of - AV block - Heart failure nous infusion of 500 μg/kg β-blocker arrhythmias and - Hypotension - Bronchospasm over 1~2 min; subsequently, - Decrease dose if hypoten- hypertension - Cardiac dysfunc- - AV block continuous intravenous infusion or bradycardia occurs. - Anoxic spells tion sion of 25~50 μg/kg/min is - Higher doses are required in tetralogy of applicable. to relieve severe anoxic Fallot - The dose can be increased spell in tetralogy of Fallot (unapproved in up to 200 μg/kg/min in resis- (no clinical experience in Japan) tant cases. Japan).

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Drug Serious adverse General dosage and generic name Indications Contraindications Comments reactions dosing method [trade name]# Flecainide - Ventricular - Heart failure - Precipitation of [Oral] - ECG monitoring is neces- [Tambocor] tachycardia - Heart block life-threatening - 2~3 mg/kg 2~3 times per sary during slow intrave- - Arrhythmias in - Hypokalemia arrhythmias day nous infusion. WPW (particularly in - Adjust dose according to - Blood concentrations is syndrome patients with blood concentrations monitored during intrave- - AV reentry structural heart [Intravenous] nous infusion continued for tachycardia disease) - Single dose 2 mg/kg more than 24 hours (effec- - Cardiac dysfunc- - 0.1~0.25 mg/kg/h until reso- tive blood concentrations tion (particularly lution of arrhythmias 200~800 μg/L) when used with (maximum total dose of β-blockers or 600 mg in first day) calcium channel blockers) Furosemide - Heart failure - Hypokalemia - Hyponatremia [Oral] - In case of oliguria, higher [Lasix] - Pulmonary - Hypotension - Hypokalemia - 0.5~2 mg/kg 2 or 3 times per doses may be required, and congestion - Hypomagnesemia day (maximum daily dose: increased gradually accord- - Hypertension - Nephrocalcinosis 12 mg/kg or 80 mg/day in ing to urine output. - Hypotension total, whichever is lower) - Hearing loss [Intravenous] (with rapid intra- - 0.5~1 mg/kg up to 4 times venous infusion) per day, or continuous infusion of 0.1~2 mg/kg/h Ibuprofen - Patent ductus - Hepatic dysfunction - Hemorrhage - 10 mg/kg by slow intrave- - Decrease dose in cases of [Brufen] arteriosus in - Pulmonary (particularly, nous infusion renal dysfunction. preterm hypertension intracranial) - The 2nd (at 24 hours) and - Monitoring of hepatic func- infants (no - Hemorrhage - Renal dysfunc- 3rd (at 48 hours) doses are tion is necessary. indication for - Necrotizing tion 5 mg/kg. neonates in enterocolitis - Necrotizing Japan) - Infection enterocolitis Indomethacin - Patent ductus - Renal dysfunction - Hemorrhage - Drip infusion over 30 minutes - Monitor urine output, and [Indacin] arteriosus in - Infection including intra- - Neonates under 48 hours after the 2nd and 3rd doses be preterm - Hemorrhage cranial hemor- birth: 200 μg/dose, followed given until urine output infants (particularly, rhage by two doses of 100 μg recovers. intracranial) - Oliguria, anuria separated by 12~24 hours - Indomethacin is used as an - Necrotizing - Fluid retention - Neonates 2~7 days after anti-inflammatory drug for enterocolitis birth: 200 μg/dose, followed post-pericardiotomy by two doses of 200 μg syndrome. separated by 12~24 hours - Neonates over 7 days after birth: 200 μg/dose, followed by two doses of 250 μg separated by 12~24 hours Isoprenaline - Bradycardia - Hypotension - Hypotension - 0.02 μg/kg/min, maximum [Proternol] - Complete AV - Tachycardia 0.5 μg/kg/min (maximum block - Arrhythmias 0.2 μg/kg/min in neonates) Lidocaine - Ventricular - AV block - Central nervous - 0.5~1 mg/kg intravenously - ECG monitoring is neces- [Xylocaine] fibrillation - Cardiac dysfunc- system depression over 1 minute. sary during therapy. - Ventricular tion - Respiratory - Repeat at 5-minute intervals - Decrease dose when there tachycardia - Hepatic failure depression up to 3 mg/kg, followed by is hepatic or renal dysfunc- - Renal failure - Hypotension continuous infusion of tion. - Bradycardia 1~3 mg/kg/h. Lisinopril - Heart failure - Renal dysfunction - Hypotension - Starting at a rate of - ACE inhibitor [Zestril, Longes] - Hypertension - Renovascular (particularly with 0.1 mg/kg/day orally - Usually used with loop disease initial doses) - The dose can be increased diuretics for heart failure. - Coarctation of - Renal dysfunc- up to 0.5~1 mg/kg/day - Do not use with potassium aorta tion according to response. sparing diuretics. - Left ventricular - Tachycardia - Maximum daily dose 40 mg - Careful observation is outflow tract - Alopecia required at the initial induction. obstruction - Persistent dry - Usually, in an in-patient to - Left ventricular cough ensure monitoring of blood inflow obstruction pressure and renal function. Losartan - Heart failure - Renal dysfunction - Hypotension - 0.5 mg/kg orally once per - Angiotensin II receptor blocker [Nu-Lotan] - Hypertension - Renovascular (particularly with day - This drug is similar to ACE disease initial doses) - The dose can be increased inhibitors in drug efficacy, - Coarctation of - Hypokalemia up to 2 mg/kg once per day. but does not cause dry aorta cough characteristic of ACE - Left ventricular inhibitor therapy. outflow tract - Decrease dose when there obstruction is renal or hepatic dysfunction. - Left ventricular - Introduce with caution inflow obstruction because of the risk of hypotension.

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Drug Serious adverse General dosage and generic name Indications Contraindications Comments reactions dosing method [trade name]# Milrinone - Heart failure - Renal failure - Arrhythmias - Continuous intravenous - PDE inhibitor with both posi- [Milrila] - Low cardiac - Hypotension - Hypotension infusion of 30~45 μg/kg/h tive inotropic and dilative output vasodilator actions - Shock - Administer 50~75 μg/kg by drip infusion over the first 1-hour period if there is no hypotension. - Decrease dose if there is renal failure. - Short-term use only. Norepinephrine - Hypotension - Hypertension - Hypertension - Continuous intravenous (Noradrenaline) secondary to - Severe vasocon- infusion of 20~100 ng/kg/min [Noradrenaline] severe vasodi- striction and - The dose can be increased lation peripheral isch- up to 1 μg/kg/min. emia - Arrhythmias Propranolol - Hypertension - Bronchial asthma - Bradycardia - Tetralogy of Fallot: - Contraindicated for use with [Inderal] - Supraventricu- - AV block - Heart failure 15~20 μg/kg intravenously; verapamil. Decrease dose if lar tachycardia - Hypotension - AV block the dose can be increased there is renal or hepatic - Ventricular - Cardiac dysfunc- - Peripheral vaso- slowly up to 100~200 μg/kg dysfunction. tachycardia tion constriction under ECG monitoring. - Anoxic spell in - Fatigue - Arrhythmias: 0.25~0.5 mg/kg tetralogy of orally 3 times per day; the Fallot dose can be increased up to 1 mg/kg 3 times per day. Slow intravenous infusion of 10~50 μg/kg under ECG monitoring Sildenafil - Pulmonary - Hypotension: - Dyspnea - 0.5 mg/kg/dose orally every - Decrease dose if there is [Revatio] hypertension Coronary artery - Headache 4~6 hours. hepatic or renal dysfunction. disease - Visual distur- - The dose can be increased - This drug is also used for bances up to 2 mg/kg every 4 hours pulmonary hypertension - Erection according to response. following cardiac surgery and for weaning from inhaled nitric oxide therapy. Sotalol - Atrial flutter - Bronchial asthma - Bradycardia - 1 mg/kg orally twice per day - Monitor the QT interval. [Sotacor] - Supraventricu- - AV block - Heart failure - The dose can be increased - Avoid use with other drugs lar tachycardia - Hypotension - Bronchospasm every 3~4 days up to that induce QT prolonga- - Ventricular - Cardiac dysfunc- - AV block 4 mg/kg orally twice per day tion. tachycardia tion - Arrhythmias if necessary - Effective blood concentra- - Hypokalemia - QT prolongation (maximum daily dose tions are 0.04~2.0 mg/L. - Hypomagnese- - Torsades de 160 mg). mia pointes - QT prolongation Spironolactone - Potassium - Hyperkalemia - Hyperkalemia - 0.5~1 mg/kg orally 3 times - Usually used with loop [Aldactone-A] sparing - Hyponatremia - Hyponatremia per day diuretics. diuretic (Anti- - Hepatic dysfunc- - Should not be given simul- aldosterone tion taneously with ACE inhibi- drug) - Gynecomastia tors. - Osteomalacia ACE, angiotensin converting enzyme; ARDS, acute respiratory distress syndrome; AV, atrioventricular; PDE, phosphodiesterase; SIADH, syndrome of inappropriate antidiuretic hormone secretion; WPW, Wolff-Parkinson-White. Adapted from, Anderson RH, et al. Paediatric cardiology, 3rd edn, 2009: 1299–1303,69 with permission from Elsevier Inc., modified for Japa- nese pediatric patients. #Added to this table.

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Circulation Journal Vol.78, February 2014