Berrueco R, Dapena JL, Sebastin E, Sastre A. You may report side effects to FDA at 1-800-FDA-1088. 2000;11 Suppl 3:273-6 Immune thrombocytopenia (ITP) in children: Management of chronic disease. Berrueco and colleagues (2018) stated that until a few years ago, splenectomy was one of the main strategies for treatment of immune thrombocytopenia (ITP) in adults and children aged more than 5 years. FDA approves romiplostim (Nplate) for the treatment of thrombocytopenia. Chao NJ. Thrombocytopenic purpura - romiplostim. 2011;157:267-288. The choice among these options is complex and is highly dependent on the values and preferences of the patient and family. Important: The drug information on this page is meant to be educational. Indicated for immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy Initial 1 mcg/kg SC qWeek Use lowest dose of Nplate to achieve. Bussel JB. Thrombocytopenia following allogeneic stem cell transplantation. MedlinePlus Information on Romiplostim - A lay language summary of important information about this drug that may include the following: Drugs are often studied to find out if they can help treat or prevent conditions other than the ones they are approved for. and transmitted securely. Cochrane Database Syst Rev. A Review of Romiplostim Mechanism of Action and Clinical Applicability. Cancer. Disclaimer, National Library of Medicine National Comprehensive Cancer Network (NCCN). "A model to predict response to romiplostim indicated that lower-risk MDS, lower baseline TPO levels (less than 500 pg/mL), and limited platelet transfusion history, had the greatest effect on subsequent platelet response to romiplostim". Soff GA, Miao Y, Bendheim G, Batista J, Mones JV, Parameswaran R, Wilkins CR, Devlin SM, Abou-Alfa GK, Cercek A, Kemeny NE, Sarasohn DM, Mantha S. J Clin Oncol. The International Prognostic Scoring System. -, Ann Oncol. Minowa K, Arai K, Kasahara M, et al. Such insertions do not conform to our. 2001;68:210-214. The authors concluded that although these findings were promising, data from randomized clinical trials are needed to fully understand the role of romiplostim after SCT. Moreover, they stated that further data are needed to provide definitive evidence of its safety for newborns. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP. Waltham, MA: UpToDate; reviewedJuly 2022. Copyright Aetna Inc. All rights reserved. Management of the hematologic complications of the myelodysplastic syndromes. 2019;3(22): 37803817. A review in UpToDate on "Management of the hematologiccomplications of the myelodysplastic syndromes" (Sekeres, 2022) discussed theclinical trial by Giagounidis et al. In 19 of 20 patients, platelet counts of 100 10 (9)/L were achieved. Using romiplostim long-term can cause harmful effects on your bone marrow that may result in serious blood cell disorders. . The https:// ensures that you are connecting to the 2004 Jan 21;25(2):52-60 2009;46(1 Suppl 2):S26-S32. Accessibility PMC What are the other precautions for Romiplostim? Short-term recommendations specific to issues with COVID-19 (SARS-CoV-2). The authors stated that the latest recommendations call for exhausting all options of medical treatment in children with chronic ITP before resorting to splenectomy, with especial emphasis on the use of TPO-Ras. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. These researchers reported a case series of 5 children treated for solid tumors where romiplostim was used without adverse effects to successfully resolve and prevent therapy-limiting refractory TRT. ICON1 is a prospective, multi-center, observational study of 120 children starting 2nd-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). Romiplostim is produced by recombinant DNA technology in Escherichia coli (E. coli). Romiplostim acts like a certain natural substance (thrombopoietin) that causes the body to produce platelets. 2022 Jul;10(3):158-163. doi: 10.14791/btrt.2022.0018. Gonzalez-Nieto JA, Martin-Suarez I, Quattrino S, et al. Ise M, Iizuka H, Kamoda Y, et al. Children aged 1 year and older who have had ITP for at least 6 months. Waltham, MA: UpToDate; reviewed January 2022. After the introduction of rituximab, pharmacological treatment started to displace surgery as a 2nd-line treatment. Am J Hematol. Drugs. Do not use romiplostim in an attempt to normalize platelet counts. Sepsis prevented continued chemotherapy in one patient. This site uses cookies to deliver our services. Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome. Pediatr Blood Cancer. 1 INDICATIONS AND USAGE 1.1 Patients with Immune Thrombocytopenia (ITP) . Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84 % to 48 %, p=0.01 and 81 % to 43 %, p=0.004) and non-skin-related bleeding symptoms (p=0.0001 andp=0.0006) after 1 month of treatment. For additional language assistance: Therapeutic, prophylactic, or diagnostic injection, Immune thrombocytopenic purpura [idiopathic], Other secondary thrombocytopenia [chemotherapy-induced thrombocytopenia], Adverse effect of antineoplastic and immunosuppressive drugs, initial encounter, subsequent encounter, or sequela, Radiation sickness, unspecified [Hematopoietic syndrome of acute radiation syndrome], Other aplastic anemias and other bone marrow failure syndromes, Purpura and other hemorrhagic conditions [thrombocytopenia associated with Evans syndrome], Graft-versus-host disease [associated with thrombocytopenia], Other diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism complicating pregnancy [thrombocytopenia], Complications of stem cell transplant [thrombocytopenia following allogeneic stem cell transplantation]. 2014;37(1):97-101. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Rates of splenectomy among children with ITP have declined considerably since the early 2000s, particularly among children < 5 years old. Vishnu P, Aboulafia DM. The site is secure. Yoshinari H, Kawahara Y, Niijima H, et al. Epub 2018 Jan 3. Homeida S, Ebdon C, Batty P, et al. Zhang J, Liang Y, Ai Y, et al. DOSAGE & INDICATIONS For the treatment of chronic immune thrombocytopenic purpura (ITP) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Objectives: The primary objective of this analysis was to confirm the appropriateness of romiplostim dose and platelet . Fifteen patients resumed cytotoxic chemotherapy with continued romiplostim support and 14 tolerated at least two subsequent cycles of chemotherapy, on schedule, without recurrence of dose-limiting CIT. In December 2018, the US FDA approved romiplostim for use in pediatric patients 1 year of age with ITP of >6 months' duration and insufficient response to corticosteroids, immunoglobulins, or splenectomy, based on similarly favorable clinical trial data. Obstet Gynecol. Waltham, MA: UpToDate;reviewed November 2021. 2018;5(3):e117-e126. This medication is a thrombopoietin (TPO) mimetic protein, prescribed for low platelets (thrombocytopenia). 2012;23(4):264-273. In adult patients at 5% higher patient incidence in Nplate versus placebo include: arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, an paresthesia; In pediatric patients at an incidence 25% include: contusion, upper respiratory tract infection, and oropharyngeal pain. NOTE: Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome or any cause of thrombocytopenia other than ITP. Lastly, splenectomy can also be considered in patients that have a poor health-related quality of life despite receiving other treatment, or at the request of the family. This site needs JavaScript to work properly. Semin Hematol. Safety and efficacy of romiplostim in splenectomized and nonsplenectomized patients with primary immune thrombocytopenia. Zhang J, Liang Y, Ai Y, et al. Eltrombopag versus romiplostim in treatment of adult patients with immune thrombocytopenia: A systematic review incorporating an indirect-comparison meta-analysis. Lancman G, Coltoff A, Steinberg A. Romiplostim for thrombocytopenia following allogeneic stem cell transplantation: A case series. 2013;28(2):335-341. Maximova et al. Romiplostim is approved by the FDA for the treatment of thrombocytopaenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins or . Nplate (romiplostim) is not FDA-approved for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP (Amgen, 2018). No universally accepted standards for the timing of splenectomy in chronic ITP exist, but the American Society of Hematology (ASH) guidelines recommend waiting until at least 12 months after the initial ITP diagnosis, if at all possible, and avoiding splenectomy for children < 5 years old. Bussel JB, Buchanan GR, Nugent DJ, et al. Thus, since the benefits of splenectomy do not seem to outweigh its disadvantages in children, this intervention should only be used in selected cases: patients who cannot tolerate or do not respond to medical treatment, including corticosteroids, immunoglobulins, TPO-RAs and even immunosuppressive therapy. -, J Thromb Haemost. 2019 Apr;25(3):567-576. doi: 10.1177/1078155217748470. -, Hematology Am Soc Hematol Educ Program. 2001 Feb 15;19(4):1137-46 An Pediatr (Barc). Romiplostim storage conditions Store it in refrigerator (2 to 8C). doi: 10.1002/14651858.CD012035.pub2. All our products are supported by strict adherence to quality and analysis certification. Blood. For patients with chronic ITP whose symptoms and risks are not adequately controlled using first-line therapies and for those who remain dependent on glucocorticoid therapy to control symptoms, second-line treatment options include rituximab, thrombopoietin receptor agonists (eltrombopag, romiplostim), and splenectomy. . NCCN hematopoietic growth factors. All comments are however constantly reviewed for spam and irrelevant material (such as product or personal advertisements, email addresses, telephone numbers and website address). Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Drugs. Thrombocytopenia in pregnancy. Language services can be provided by calling the number on your member ID card. Vadhan-Raj S. Management of chemotherapy-induced thrombocytopenia: Current status of thrombopoietic agents. Drug Des Devel Ther. Grace and associates (2019) noted that while many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). Please enable it to take advantage of the complete set of features! 10/27/2022 2008;8(7):1021-1030. Int J Hematol. Neunert C, Lim W, Crowther M, et al. Splenectomy is effective in improving the platelet count and reducing the associated risk of bleeding in 60 to 80 % of children with chronic ITP. Myelodysplastic syndromes, for lower risk disease in patients with severe or refractory thrombocytopenia following disease progression or no response to hypomethylating agents,immunosuppressive therapy, or clinical trial, Chemotherapy-induced thrombocytopenia (CIT). Medindia 2016 Jan;172(2):262-73. doi: 10.1111/bjh.13827. Indications. Blood Adv2019;3(23):38293866. Mowatt G, Boachie C, Crowther M, et al. This patient information sheet applies only to approved uses of the drug. Purpose: Romiplostim decreases your risk of bleeding by increasing the number of platelets. Romiplostim side effects Dizziness, headache, indigestion, joint pain, muscle tenderness or weakness, shoulder pain, stomach pain or upset, and trouble in sleeping. Common Drug Review. However, due to the early drug discontinuation, interpretation of these datais limited." Additionally, romiplostim was well-tolerated overall; 1 patient developed minimal fibrotic changes on bone marrow biopsy post-romiplostim. 2012;48(4):293-301. Your treatment with romiplostim. Medscape [online]. Brain Tumor Res Treat. Background: The clinical course of immune thrombocytopenia (ITP) can be categorized into three phases: newly diagnosed (<3 months post-diagnosis), persistent (3-12 months) or chronic (>12 months). 2008;68(7):901-912. Nuenert C, Terrel DR, Arnold DM, et al. official website and that any information you provide is encrypted 2018;13(6):e0198504. Signs include unusual fatigue, shortness of breath with exertion, pallor, and bruising. 89) were not significantly different between the two groups. Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: Results from two randomized, placebo-controlled trials. 63, 74-76 in pediatric populations, platelet responses were observed up to 24 weeks in clinical trials 77, The editorial team reserves the right to review and moderate the comments posted on the site. Bose P, Hussein KK, Terrell DR, et al. 2014;22(5):1217-1222. J Blood Med. This page contains brief information about romiplostim and a collection of links to more information about the use of this drug, research results, and ongoing clinical trials. Scottish Medicines Consortium. Cancer. Romiplostim injection is used to treat low blood platelet counts (thrombocytopenia) and help prevent bleeding in patients with a blood disorder called immune thrombocytopenia (ITP). IPSS (International Prognostic Scoring System), IPSS-R (Revised International Prognostic Scoring System). 1. Do not freeze. CEDAC Final Recommendation. Always seek the advice of a qualified physician for medical diagnosis and treatment. Curr Opin Oncol. Chemotherapy-induced thrombocytopenia (CIT) can cause delay or reduction in subsequent courses of chemotherapy. Other diagnoses/indications. The use of second-generation thrombopoietic agents for chemotherapy-induced thrombocytopenia. Bone Marrow Transplant. Giagounidis A, Mufti GJ, Fenaux P, et al. U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Office of Oncology Drug Products (OODP). studied romiplostim for the treatment of CIT. Nplate (romiplostim) for injection is supplied as a sterile, preservative-free, solid white lyophilized powder in single-dose vials that deliver 125 mcg (NDC-55513-223-01), . Nplate is indicated for the treatment of thrombocytopenia in: Adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The mean dose of romiplostim to achieve adequate platelet recovery was 2.9 mcg/kg (range 1.0-5.1). Rodeghiero F, Stasi R, Gernsheimer T, et al. Nplate is supplied as either 125 mcg per vial, 250 . UpToDate [online serial]. London, UK: NICE; March 30, 2010. Treatment of Primary Immune Thrombocytopenia (ITP) Treatment. Results: Romiplostim improved platelet counts in all 20 patients. Pediatric patients 1 year of age and older with ITP for at least 6 months who have had an insufficient We have discussed the latest FDA-approved agent, romiplostim, as . . This medicine is used after a splenectomy (surgery to remove the spleen) or when other medicines (eg, steroids or immunoglobulins) have not worked well enough in . 2011;2011:384-90 Waltham, MA: UpToDate; reviewed June 2022. Caution should be exercised in patients with history of kidney or liver impairment, bone marrow depression, blood cancer, (eg, myelodysplastic syndrome [MDS]), blood clotting or bleeding problems, heart attack, stroke, blood clots, who are taking other medications, any allergy, children, elderly, during pregnancy and breastfeeding. Off-Label Use of Thrombopoietin Receptor Agonists: Case Series and Review of the Literature. Systematic literature review and meta-analysis on use of Thrombopoietic agents for chemotherapy-induced thrombocytopenia. For adults with immune thrombocytopenia (ITP) Strive for stability, Reach for Remission When steroids stop working well enough, once-weekly Nplate (romiplostim) has been proven to provide platelet stability and the possibility to stop treatment* * Remission was a secondary objective in the Nplate clinical study. This Clinical Policy Bulletin may be updated and therefore is subject to change. Support Care Cancer. Last Review10/27/2022. Parameswaran R, Lunning M, Mantha S, et al. Ruiz-Delgado GJ, Lutz-Presno J, Ruiz-Argelles GJ. However, much of the information may also apply to unapproved uses that are being studied. There are 3 main prognostic scoring systems used in MDS: The IPSS is a commonly used tool in MDS which uses prognostic indicators to assign a risk score, and risk group,to help predict the course of disease. Sekeres MA, Kantarjian H, Fenaux P, et al. Gastrointestinal disorders: Gastroenteritis, nausea, diarrhoea, constipation, abdominal pain, dyspepsia. Having previously been restricted to use in patients with chronic ITP, romiplostim (a thrombopoietin receptor agonist) was recently approved in the USA and Europe for use across all phases of . 2014;120(12):1838-1846. 2016;7:99-106. angioedema, urticaria). 2017 Nov 27;11(11):CD012035. What's New from OODP. Prescribing Information. However, studies that compare both therapeutic options have yet to be conducted. Lower-risk MDS tends to grow and progress slowly, thus,a lower-risk scoregenerally indicates a better outlook. Our Pharma Division deals only with the best, GMP certified generics and branded medication for the export market. There are a number of available 2nd-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. We performed a retrospective review of the use of romiplostim for dose-limiting CIT at Memorial Sloan-Kettering Cancer Center from 2010-2012. After failure of first-line treatments, the teratogenicity and toxicity of other therapeutic agents limit the available options and treatment. You may have severe complications or die from some forms of blood clots, such as clots that spread to the lungs or that cause heart attacks or strokes. National Comprehensive Cancer Network, Inc. Find Clinical Trials for Romiplostim - Check for trials from NCI's list of cancer clinical trials now accepting patients. (romiplostim) for injection, for subcutaneous use . Advise women not to breastfeed during treatment with this drug. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Please note for the minimum order for Exports is of US$ 100. Plymouth Meeting, PA: NCCN; August 2022. Controversies in the treatment of paediatric immune thrombocytopenia. Thus, despite a good initial response (70 to 85 % of cases) and the fact that most patients maintain a normal platelet count 5 years post-intervention (60 to 70 % of cases), one cannot ignore the associated morbidity: the risk of infection in splenectomized patients is as high as 11 to 16 % even with correct vaccination and administration of antibiotic prophylaxis, the proportion of patients that develop thrombosis after surgery ranges between 1.6 and 4.3 %, and the risk of severe intra-operative or post-operative hemorrhage is of 0.78 %. These investigators described the cases of 2 pregnant patients with corticosteroid-refractory immune thrombocytopenia who were successfully treated by romiplostim without any fetal or maternal complications. Canadian Agency for Drugs and Technologies in Health (CADTH). Background: Romiplostim, a subcutaneous treatment for adult ITP, uses a platelet response-guided dose adjustment algorithm (USPI dosing, Table 1) to maintain patients' platelet count (PC).Romiplostim was recently approved for patients with ITP 12 months from diagnosis. 2022 Jun 9;17(6):e0257673. Nplate (romiplostim) is used to treat low blood platelet counts in adults with chronic immune (idiopathic) thrombocytopenia (ITP), when certain other medicines, or surgery to remove the spleen, have not worked well enough. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated withromiplostimor placebo in a randomised double-blind trial. 250 mcg or 500 mcg of deliverable romiplostim in single-use vials ( 3) Decroocq et al. Thrombotic/Thromboembolic Complications NCCN Drugs & Biologics Compendium. Health Technol Assess. government site. PLoS One. Sekeres MA. in adults, romiplostim increased platelet counts and reduced the rate of bleeding events in multiple phase 1, 2, and 3 clinical trials for up to 52 weeks 61, 62, 72, 73 and long-term extension studies or pooled analyses for up to 5.4 years. International consensus report on the investigation and management of primary immune thrombocytopenia. J Gastroenterol Hepatol. Tiu RV, Sekeres MA. sharing sensitive information, make sure youre on a federal 2022 Jun 1;107(6):1243-1263. doi: 10.3324/haematol.2021.279512. The authors concluded that prospective studies on this use of romiplostim are needed. Careers. Romiplostim for secondary thrombocytopenia following allogeneic stem cell transplantation in children. No treatment-related toxicity was observed, but this would need to be confirmed in a larger, prospective trial. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Regulatory Status FDA-approved indications: Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in: (1) 1. Coverage Indications, Limitations, and/or Medical Necessity. 2011;117(16):4190-4207. 2017;64(8). WPSS (WHO classification-based Prognostic Scoring System). Advise patients to avoid situations that may increase the risk of bleeding. Edinburgh, Scotland: NHS Scotland: September 4, 2009. Romiplostim is used in certain patients with ITP who have not gotten better with other treatment. Appraisal Consultation Document. Adult patients with immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy; Pediatric patients 1 year of age or older with ITP for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. If patients resumed chemotherapy, weekly romiplostim was continued. Managing Side Effects of Cytotoxic Chemotherapy in Patients With High Grade Gliomas. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. NCCN does point out that romiplostim is not currently approved for use in persons with MDS. Immune system disorders: Hypersensitivity reactions (e.g. UpToDate [online serial]. 2021 Sep 28;11:680411. doi: 10.3389/fonc.2021.680411. While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (p =0.04). No resistance to romiplostim was observed. 2009;144(3):409-415. Person'swith higher scores (e.g., intermediate-2 and high risk; IPSS 1.5) are at higher risk of transformation to acute myelogenous leukemia. Kuter DJ, Bussel JB, Lyons RM, et al. Blood Adv. Nplate (romiplostim) is FDA-approved in pediatric patients 1 year of age and older with ITP for at least 6 months and who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy (Amgen, 2018). NCCN Clinical Practice Guidelines in Oncology, Version 3.2022. Drug Information 2012;47(9):1154-1163. National Comprehensive Cancer Network (NCCN). 2021 May 26;15:2243-2268. doi: 10.2147/DDDT.S299591. Refer to the off-label use policy for the relevant line of business if diagnosis is NOT Comments should be on the topic and should not be abusive. Seketes states that romiplostim should not be used routinely in MDS based on this clinical trial; however, it appears reasonable to consider use in patients with bleeding due to low platelet counts who do not respond to transfusions and in whom aminocaproic acid has been unsuccessful. The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes. Bookshelf Unable to load your collection due to an error, Unable to load your delegates due to an error. Romiplostim. . Am J Hematol. 2010;115(2):168-186. Treating providers are solely responsible for medical advice and treatment of members. Blood. Romiplostim was initiated at 1-2 mcg/kg weekly, with dose escalation by 1 mcg/kg per week until recovery of platelets ( 100 10(9)/L). Call your doctor for medical advice about side effects. The International Prognostic Scoring System, IPSS-R Myelodysplastic Syndrome Risk Assessment Calculator. Waltham, MA: UpToDate;reviewedJanuary 2022. Although splenectomy is effective in most patients, it is also associated with substantial risks, especially overwhelming sepsis. Romiplostim should be used only when the degree of thrombocytopenia and clinical condition increase the risk for bleeding; . Romiplostim. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Profession (construction worker) or lifestyle (e.g., plays contact sports) that predispose member to trauma. The study drug, romiplostim, was discontinued early because of the potential risk for disease progression to AML. what you should tell your doctor before using this drug. Patients and methods: Examples of Risk Factors for Bleeding (not all inclusive): Prognosis ofindividuals with MDS can be calculated using a number of scoring systems. Romiplostim is an Fc-peptide fusion protein that binds to and activates the thrombopoietin (TPO) receptor, thereby increasing platelet production. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Source: Leukemia & Lymphoma Society. At present, many experts recommend the use of receptor agonists (TPO-Ras; eltrombopag and romiplostim) in patients that do not respond to initial treatment with corticosteroids and immunoglobulin before the use of rituximab and surgery. Am J Hematol. Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia. Sixteen patients achieved platelet recovery by 2 weeks. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.
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