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] Circulation Journal Vol.78, February 2014 508 JCS Joint Working Group 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 concentra- tion, 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