Expert consensus on the off-label use of drugs for pediatric rare diseases in China (2025 edition)

Introduction

The package inserts, serving as a critical reference for clinical medication, constitute the legal standard guiding physicians and pharmacists in the rational use of pharmaceuticals. Off-label drug use refers to the administration of medications beyond the scope defined by the drug label and instruction manual, as approved by national regulatory authorities, encompassing but not limited to unapproved indication, dosage, dosing frequency, the course of treatment or population (1). The rapid advancement of diagnostic and therapeutic technologies for rare diseases, coupled with the relatively delayed updates to package inserts, has made off-label drug use a prevalent practice in clinical settings (2). In pediatric rare diseases, off-label drug use is often unavoidable due to systemic challenges: (I) limited treatment options: low disease prevalence and insufficient research and development incentives result in a paucity of pediatric-specific clinical data and approved drugs for children; (II) data scarcity: ethical restrictions on pediatric trials necessitate heavy reliance on extrapolated adult data; (III) prolonged drug development: complex pathogenesis and children’s distinct physiology extend drug development cycles, causing regulatory delays; (IV) high clinical urgency: significant risks of disability and mortality compel the use of therapies that, although unapproved, may offer potential therapeutic benefits. The Chinese “Law on Doctors” provides a legal framework and safeguards for off-label drug use (3). However, the inappropriate use of medications off-label poses substantial clinical and safety risks (4). To date, no comprehensive guidelines or expert consensus exist regarding off-label drug use for pediatric rare diseases in China. To address this gap, and to promote standardized and rational medication practices, the Rare Disease Expert Committee of the Guangdong Pharmaceutical Association has developed the “Expert consensus on the off-label use of drugs for pediatric rare diseases in China (2025 edition)” (hereafter referred to as the “Consensus”). This document aims to provide evidence-based medical guidance for the off-label use of commonly prescribed drugs in pediatric rare disease treatment, standardize off-label drug use practices, and enhance pharmaceutical monitoring pharmacovigilance in this vulnerable population.

Methods

The consensus scope and target population

This consensus is applicable to healthcare institutions across all levels for the treatment of pediatric rare diseases. The target patient population encompasses individuals under younger than 18 years diagnosed with conditions listed in the First or Second Batch of China’s Rare Disease Catalog (5,6). The rare diseases and off-label drugs covered in this consensus are listed in Table S1. The target healthcare professionals for this consensus include physicians, pharmacists, nurses, and policymakers engaged in managing rare diseases.

The methodology of the consensus development

Using a nominal group technique, an experienced moderator guided 48 domain experts in structured discussions on the off - label use of drugs for pediatric rare diseases. The consensus development and reporting processes were conducted in strict accordance with established guidelines, including the World Health Organization (WHO) Handbook for Guideline Development (2nd edition, 2014) (7), the Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement (8), and the evidence-based pharmaceutical evaluation methods for off-label drug use (9). Potential conflicts of interest and disclosure management were addressed following the International Committee of Medical Journal Editors’ Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals.

Consensus panels

The group members comprised experts from the following disciplines: clinical physician, pharmacist, and pharmaceutical administration. The composition and positions of the panel members are shown in Table S2.

Evidence retrieval and data extraction

The “Consensus” document systematically compiles drugs frequently used off-label for the treatment of pediatric rare diseases. The document is presented in a tabular format to enhance clarity and is organized according to therapeutic applications. The selection criteria for these drugs are derived from the “2024 Guangdong Pharmaceutical Association Off-Label Drug Use Directory” (10), with adjustments for the unique aspects of rare disease medications:

• Included in the package inserts of the United States, European Medicines Agency (EMA), or the United Kingdom;
• Listed in the “Chinese Pharmacopoeia Clinical Medication Instructions”, “Clinical Diagnosis and Treatment Guidelines” (published by the Chinese Medical Association and People’s Medical Publishing House), or included in official documents issued by the National Medical Products Administration or the National Health Commission of China;
• Included in leading international and Chinese guidelines or consensus documents;
• Rated by Micromedex^® with an efficacy rating and recommendation level IIb or evidence level C or higher;
• Supported by published randomized controlled trials in first-quartile (Q1) Science Citation Index (SCI) journals within the relevant field; for anti-tumor agents, support should be provided by observational studies or confirmatory clinical trials demonstrating clinical benefits, published in Q1 SCI journals.

The extraction procedure was independently performed by two investigators to ensure methodological rigor. Following the completion of the extraction process, the obtained results were systematically cross-verified. In instances where discrepancies were identified during the extraction phase, these were thoroughly deliberated upon, and a consensus was achieved either through mutual agreement or by arbitration conducted by a third independent researcher.

The formulation and revision of consensus

The writing committee developed evidence-based recommendations through a systematic review of the current literature. Following extensive deliberations among subject matter experts, which involved a rigorous evaluation of the available evidence base and its alignment with current clinical practices, the initial draft of the expert consensus statement was systematically developed. Subsequently, guideline committee members critically evaluated and provided substantive feedback on the consensus, culminating in the establishment of a finalized consensus.

The “Consensus” is structured in a tabular format to enhance clarity and conciseness. Each entry in the consensus table includes the following elements: “Generic Name” (drug’s official generic designation), “Dosage Form”, “Off-label content” (type of off-label use) including “Indication” and “Population”, “Specific usage and dosage” (outlining the dosage and administration details for off-label use), “Evidence and References” (citations that support off-label use), and “Evidence Level” (Micromedex).

Results

Off-label drug use for pediatric Alport syndrome (AS) treatment

AS is a syndrome characterized by clinical manifestations of hematuria, proteinuria, and progressive renal function decline, and some patients also show extrarenal symptoms such as sensorineural hearing loss and ocular lesions (11). AS has been reported to affect around one in 5,000 individuals and accounts for 0.5% of newly diagnosed end-stage renal disease cases among adults and 12.9% among children (12,13). There is currently no radical therapy for AS. The treatment with renin-angiotensin-aldosterone system (RAAS) blockers, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB) and aldosterone antagonists, is recommended to delay the progression of renal failure (14). There is a randomized, placebo-controlled study (phase III) in children with AS, which shows that ramipril (an ACEi) is safe and suggests a significant reduction in the risk of disease progression when started early (15). A recent data from Huang et al. confirms that early initiation of RAAS blockade in pediatric AS is linked to slower progression of kidney disease (16). It is recommended that male patients with X-linked AS, patients with autosomal recessive AS, and patients with digenic AS who are older than 12 months should initiate the treatment with RAAS blockers upon diagnosis (17). For female patients with X-linked AS and patients with autosomal dominant AS who are over 12 months old, it is recommended that they start the treatment with RAAS blockers when trace albuminuria is repeatedly detected, if infection has been excluded (17). Table 1 presents the expert consensus on the off-label use of drugs to treat pediatric AS.

Off-label drug use for pediatric autoimmune encephalitis (AE) treatment

AE represents a spectrum of neuroinflammatory disorders mediated by autoantibodies directed against neuronal cell surface or synaptic proteins, resulting in impaired neuronal function. Among the various subtypes, anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) predominates, accounting for approximately 54–80% of AE cases, with leucine-rich glioma inactivated protein 1 (LGI1) antibody-associated encephalitis and gamma-aminobutyric acid B type receptor (GABABR) antibody-associated encephalitis being the subsequent most common forms (19). NMDARE predominantly manifests in pediatric and young adult populations. NMDARE exhibits an incidence rate of 0.17 cases per 100,000 individuals, with the majority of patients demonstrating a favorable clinical prognosis (20). Nevertheless, acute-phase mortality rates range between 5% and 10%, and a subset of patients may develop persistent neurocognitive and psychiatric sequelae (20). The therapeutic approach to AE is primarily immunomodulatory, structured into three distinct phases: first-line immunotherapy, second-line immunotherapy, and maintenance immunotherapy. First-line therapeutic interventions include corticosteroids (e.g., intravenous methylprednisolone), and/or intravenous immunoglobulin (IVIg), therapeutic plasma exchange (TPE) (20). For patients exhibiting inadequate clinical response (no clear improvement in function and the score on the Pediatric Modified Rankin Scale is ≥4 with no decrease) after approximately two weeks of two or more first-line therapies, second-line treatments such as rituximab, cyclophosphamide, or intravenous/intrathecal methotrexate are recommended. In cases of refractory NMDAR encephalitis, escalation to tocilizumab is advised. Maintenance immunotherapy is not routinely recommended; however, in pediatric patients with relapsed NMDAR encephalitis, IVIg may be considered as a maintenance option. Alternative agents for relapsed NMDAR encephalitis in pediatric patients include mycophenolate mofetil, azathioprine, and methotrexate, which may also be considered. It should be noted that none of these therapeutic agents have been approved for AE treatment. Table 2 presents the expert consensus on the off-label use of drugs to treat pediatric NMDARE.

Off-label drug use for pediatric congenital hyperinsulinism (CHI) treatment

CHI represents a heterogeneous group of genetic disorders characterized by persistent hypoglycemia resulting from dysregulated insulin secretion, distinct from acquired hyperinsulinemic conditions such as insulinoma, postprandial hyperinsulinemia, or iatrogenic insulin overdose. CHI manifests in two distinct clinical forms: a transient variant, typically resolving by 3 to 4 months of age, and a persistent form characterized by prolonged duration (22). The estimated incidence ranges from 1 in 50,000 to 1 in 30,000 live births, though comprehensive epidemiological data specific to the Chinese population remain to be established (23). Hypoglycemia can lead to irreversible severe brain damage, with the incidence of sequelae ranging from 25% to 50%, and may even result in death if not treated promptly (24). The fundamental therapeutic objective in CHI management is the maintenance of plasma glucose concentrations within appropriate physiological ranges (3.9–5.6 mmol/L) through intravenous glucose administration, thereby mitigating the risk of hypoglycemia-induced neurological sequelae (25). Diazoxide is a potassium channel agonist targeting pancreatic β-cell KATP channels, as the first-line pharmacological intervention, which has been approved for pediatric CHI in China. In cases of diazoxide intolerance or resistance, alternative therapeutic modalities including octreotide, glucagon, nifedipine, lanreotide, and sirolimus have been employed with varying degrees of efficacy (26). Table 3 presents the expert consensus on the off-label use of drugs for pediatric CHI.

Off-label drug use for juvenile generalized myasthenia gravis (MG) treatment

MG is a rare autoimmune disorder mediated by antibodies targeting antigenic determinants at the neuromuscular junction, predominantly the acetylcholine receptor (AChR), and less frequently, muscle-specific tyrosine kinase (MuSK) or lipoprotein-related protein 4 (LRP4). The age and sex adjusted incidence of MG was 0.68 per 100,000 person-years in China (27). A population-based study conducted in Southern China revealed that 45% of MG cases manifest during childhood (<14 years) (28). Juvenile MG, defined as the onset of MG in individuals under 18 years of age, is predominantly characterized by ocular involvement and rarely progresses to generalized MG. Acetylcholinesterase inhibitors, particularly pyridostigmine bromide, is recommended as first-line therapy for all subtypes of MG, and has been approved for treatment of MG in adults in China (29). Immunotherapy is applicable to patients who have failed to achieve therapeutic goals despite optimal symptom management, including intravenous IVIg, glucocorticoids, immunosuppressants, biologics and plasma exchange (29). In China, several immunotherapeutic agents, including azathioprine, cyclophosphamide, eculizumab, ravulizumab, rozanolixizumab and efgartigimod alfa, have been approved for MG treatment. Notably, eculizumab, ravulizumab, rozanolixizumab, and efgartigimod alfa are specifically indicated for adults with generalized MG and are used off-label in pediatric patients. There are no formal guidelines for the use of immunosuppressive therapy in juvenile MG and current practice has been taken from adult guidelines and expert opinions based on individual experience (29,30). Table 4 presents the expert consensus on the off-label use of drugs for juvenile generalized MG.

Off-label drug use for pediatric Wilson disease (WD) treatment

WD, also referred to as hepatolenticular degeneration, is an autosomal recessive disorder of copper metabolism resulting from mutations in the ATPase copper transporting beta (ATP7B) gene, which leads to pathological copper accumulation primarily in the liver and brain, as well as other organs (35). Epidemiological data from Germany and Japan report WD prevalence rates of 29 and 33 cases per 1,000,000 individuals, respectively, while studies in China indicate a higher prevalence of 58.7 cases per 1,000,000 (36-38). Although WD can present at any age, it is most frequently diagnosed in pediatric and adolescent populations (39). Management of WD requires lifelong intervention, with therapeutic strategies encompassing pharmacological agents and, in severe cases, liver transplantation. Pharmacological treatments are classified into two main categories: copper chelators and intestinal copper absorption inhibitors (40). These agents function through distinct mechanisms but share the common therapeutic goal of reducing systemic copper accumulation and maintaining a negative copper balance. In China, D-penicillamine, dimercaptosuccinic acid, and trientine have been approved for WD treatment. Current clinical guidelines recommend initial treatment for symptomatic patients with WD should include a chelating agent (D-penicillamine or trientine), while zinc or chelators may be used for either asymptomatic patients without signs of significant liver involvement or those in maintenance therapy (40-42). Table 5 presents the expert consensus on the off-label use of drugs for pediatric WD.

Off-label drug use for pediatric hyperphenylalaninemia (HPA) treatment

HPA represents a group of prevalent amino acid metabolism disorders primarily attributed to deficiencies in phenylalanine hydroxylase (PAH) or its essential coenzyme, tetrahydrobiopterin (BH4), leading to elevated blood phenylalanine (Phe) levels. Etiologically, HPA is classified into two major categories: PAH deficiency and BH4 deficiency, both inherited as autosomal recessive traits. Epidemiological analysis of neonatal screening data from 35 million births in China [1985–2011] identified an HPA prevalence of 1:10,397 (43). Clinically, management strategies focus on maintaining Phe concentrations within target ranges through Phe-restricted dietary regimens, often combined with pharmacological interventions (43). For PAH deficiency, a Phe-restricted diet remains the cornerstone of treatment, while adjunctive therapy with BH4 (sapropterin) may benefit patients with suboptimal Phe control due to dietary noncompliance. In cases of BH4 deficiency, sapropterin is the primary therapeutic option for patients with GTP cyclohydrolase I deficiency (GTPCHD), 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency, and pterin-4α-carbinolamine dehydratase (PC) deficiency. Additionally, most patients with PTPS deficiency and dihydropteridine reductase (DHPR) deficiency require combination therapy with L-Dopa/decarboxylase inhibitors and 5-hydroxytryptophan. Table 6 presents the expert consensus on the off-label use of drugs for pediatric HPA.

Off-label drug use for pediatric idiopathic pulmonary arterial hypertension (PAH) treatment

PAH represents a multifactorial vascular disorder characterized by increased pulmonary vascular resistance resulting from vasoconstriction and structural remodeling of the pulmonary vasculature. Epidemiological data indicate that the annual incidence of pediatric PAH in Europe ranges from 4 to 10 cases per million, with a prevalence of 24–40 cases per million, while in the United States, the annual incidence is 5–8 cases per million, with a prevalence of 26–33 cases per million (46-48). The WHO has classified pulmonary hypertension into five distinct groups based on clinical and pathophysiological characteristics (49). Idiopathic PAH (IPAH), a rare but highly heritable and fatal condition, is defined as pre-capillary PAH of unknown etiology and constitutes up to 70% of all PAH cases (50). In a national multicenter prospective registry (China, 2009–2019), 247 children aged 3 months to 18 years with PAH were analyzed; 37.7% had IPAH or heritable PAH (HPAH), while 61.5% had PAH associated with congenital heart disease (CHD) (51). In another study of 170 Chinese children with IPAH/HPAH at a tertiary center, genetic testing identified pathogenic variants in ~64% of them (mainly in BMPR2, ACVRL1, TBX4). The 1-, 3-, and 5-year survival rates in that cohort were 93.4%, 86.7%, and 68.6%, respectively. Patients with pathogenic variants had significantly worse outcomes (52). IPAH patients exhibit significantly worse survival outcomes compared to those with PAH associated with CHD (50). Current therapeutic strategies focus on three key pathogenic pathways in PAH: prostacyclin analogs, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. Data demonstrate improved survival rates with the use of these targeted therapies (53). In China, several targeted drugs, including bosentan, ambrisentan, macitentan, sildenafil, riociguat, treprostinil, and selexipag have been approved for PAH treatment. Notably, bosentan is the only agent approved for pediatric use (≥3 years), while the remaining therapies are exclusively approved for adult patients. Table 7 presents the expert consensus on the off-label use of drugs for pediatric IPAH.

Off-label drug use for pediatric Langerhans cell histiocytosis (LCH) treatment

LCH is a rare hematological disorder characterized by local or generalized, uncontrolled proliferation and infiltration of Langerhans type of histiocytic cells (58). As the most prevalent histiocytic disorder, the annual incidence of LCH has been reported at 2.6–8.9 cases per million children, more prevalent in children than adults (59). Although clinical outcomes have improved significantly in recent decades, the progression-free survival rate for high-risk patients remains suboptimal, consistently below 50% (58). Therapeutic approaches are stratified according to disease extent and severity at presentation, with current standard treatments primarily involving corticosteroids and cytostatic agents, particularly vinca alkaloids (60). For patients with suboptimal response to first-line therapy, salvage regimens using high-dose nucleoside analogs (e.g., cladribine or cytarabine) may be effective but are associated with substantial toxicity (60). Notably, emerging therapeutic strategies, including mitogen-activated protein kinase (MAPK) inhibitors, have shown promise in managing severe and refractory cases (61). However, it is important to highlight that no pharmacological agents have yet received regulatory approval for LCH treatment in China. Table 8 presents the expert consensus on the off-label use of drugs for pediatric LCH.

Off-label drug use for pediatric Leber hereditary optic neuropathy (LHON) treatment

LHON represents a rare maternally inherited disorder characterized by painless, sequential bilateral central vision loss, primarily attributed to mitochondrial DNA (mtDNA) mutations that induce retinal ganglion cell degeneration. The disease is predominantly associated with three primary mtDNA point mutations: m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6) (65). Notably, the m.11778G>A mutation accounts for 90.2% to 92.8% of cases among Chinese patients (66). Although LHON can manifest at any age, its onset most frequently occurs between 10 and 30 years. Epidemiological studies reveal significant regional variability in LHON prevalence, with estimates of 1 in 31,000 individuals in North East England and 1 in 54,000 in Denmark (67). To date, no definitive cure exists for LHON, and clinical management mainly aims to preserve residual vision and support quality of life. Emerging therapeutic strategies under investigation include mitochondrial antioxidants, gene therapy, mitochondrial replacement, and stem cell therapy (68). Among these, idebenone, a mitochondrial antioxidant, received approval from the European Medicines Agency in June 2015 for the treatment of visual impairment in LHON patients, based on robust clinical evidence (69). In China, idebenone is not yet formally approved for LHON and is used off-label. A randomized controlled trial registered in China is currently underway, which aims to evaluate the efficacy and safety of idebenone in the treatment of LHON (ChiCTR2200059044). Table 9 presents the expert consensus on the off-label use of drugs for pediatric LHON.

Off-label drug use for pediatric multiple sclerosis (MS) treatment

MS is a chronic immune-mediated inflammatory disorder characterized by demyelination within the central nervous system (CNS), exhibiting both temporal and spatial dissemination of lesions. While MS predominantly affects young adults, pediatric cases are also reported, a comprehensive meta-analysis encompassing 13 epidemiological studies has estimated the global annual incidence of pediatric-onset MS to be 0.87 cases per 100,000 individuals (71). Notably, pediatric-onset MS appear to be associated with a higher relapse frequency compared to adult-onset MS (72). In the acute phase, therapeutic strategies such as corticosteroids, plasma exchange, and intravenous IVIg are recommended to mitigate symptom severity, shorten relapse duration, and limit disability progression (73). Early initiation of disease-modifying therapies (DMTs) has been shown to reduce relapse rates and slow disease progression (74). DMTs for adult MS patients are frequently utilized in pediatric MS cases. However, the evidence base remains limited, as comprehensive data from large pediatric cohorts are currently unavailable. In China, several DMTs, including teriflunomide, fingolimod, siponimod, ozanimod, dimethyl fumarate, ofatumumab, glatiramer acetate, and interferon beta have been approved for MS treatment. However, only teriflunomide and fingolimod are currently approved for pediatric use, specifically for children aged 10 years and older in China. Table 10 presents the expert consensus on the off-label use of drugs for pediatric MS.

Off-label drug use for neonatal diabetes mellitus (NDM) treatment

NDM represents a rare monogenic form of diabetes, typically presenting within the first six months of life, with a subset of cases emerging between 6 to 12 months of age. The condition occurs with an estimated prevalence of 1 in 300,000–500,000 live births (76,77). Clinically, NDM is categorized into two distinct subtypes based on disease progression: permanent NDM and transient NDM. NDM arises from diverse genetic mutations, predominantly those affecting the development and/or functionality of pancreatic beta cells, leading to critically reduced or undetectable plasma insulin levels (78). Heterozygous mutations in the KCNJ11 and ABCC8 genes, which encode the subunits of the ATP-sensitive potassium (K_ATP) channel, are implicated in approximately 50% of permanent NDM cases (79). Initial management of neonates typically involves insulin therapy, with sulfonylureas serving as a viable alternative for select patients. Notably, approximately 90% of patients with permanent NDM caused by KCNJ11 or ABCC8 mutations respond favorably to sulfonylurea treatment, which often allows discontinuation of insulin and improves glycemic control (79). A systematic review and meta-analysis including ~285 patients with K_ATP channel mutations reported a pooled success rate of ~90.1% [95% confidence interval (CI): 85.1–93.5%] when transitioning from insulin to oral sulfonylureas (80). Significant reductions in HbA1c were observed. Mild side-effects (mostly gastrointestinal) were the most common adverse events. In China, a study has shown effectiveness and safety of sulfonylurea therapy when initiated during infancy, even before genetic results are fully available (81). Glibenclamide, the most widely used sulfonylurea in this setting, is available as an oral suspension (AMGLIDIA) approved by the European Medicines Agency specifically for NDM (82). Glibenclamide is not yet approved for use in the pediatric population in China. For other forms of permanent NDM, insulin remains the sole therapeutic option. Table 11 presents the expert consensus on the off-label use of drugs for NDM.

Off-label drug use for pediatric sickle cell disease (SCD) treatment

SCD is a group of inherited hemoglobinopathies characterized by mutations that affect the beta-globin chain of hemoglobin, which affects approximately 100,000 people in the USA and more than 3 million people globally (84,85). SCD is characterized by a complex pathophysiology involving hemoglobin polymerization, erythrocyte sickling, chronic hemolysis, hemorheological disturbances, and subsequent multi-organ damage (86). The disease manifests clinically as chronic hemolytic anemia, recurrent vaso-occlusive crises, progressive end-organ dysfunction, and both acute and chronic pain syndromes. Hydroxyurea is the first Food and Drug Administration (FDA)-approved DMT for SCD, while recent clinical trials have led to the approval of three additional therapeutic agents: L-glutamine, voxelotor and crizanlizumab, which demonstrate efficacy in reducing acute pain episodes and ameliorating chronic anemia (L-glutamine, ClinicalTrials.gov registration number: NCT01179217; location: United States; study population age range, 5–58 years) (voxelotor, ClinicalTrials.gov registration number: NCT02850406; location: United States, Lebanon and the United Kingdom; study population age range, 4–11 years) (crizanlizumab, ClinicalTrials.gov registration number: NCT01895361; location: United States, Brazil and Jamaica; study population age range, 16–65 years) (87,88). Notably, hydroxyurea remains the only disease-modifying drug with established long-term safety and efficacy data in children, while the evidence for newer agents in pediatric populations is still limited. However, voxelotor was voluntarily withdrawn from the market by the manufacturer due to safety concerns (89). Table 12 presents the expert consensus on the off-label use of drugs for pediatric SCD.

Off-label drug use for pediatric Silver-Russell syndrome (SRS) treatment

SRS is a clinically and genetically heterogeneous disorder initially described by Silver and Russell, characterized by severe intrauterine and postnatal growth retardation accompanied by diverse clinical manifestations, including hemihypertrophy, relative macrocephaly, fifth finger clinodactyly, and triangular facies (92,93). The global incidence of SRS is estimated to range between 1:30,000 and 1:100,000 (94). In ~60% of clinically diagnosed SRS patients, an (epi)genetic cause is identified (95). SRS is molecularly heterogenous, the most prevalent molecular mechanisms involve loss of methylation at chromosome 11p15 and maternal uniparental disomy for chromosome 7 (94). SRS manifests as a broad spectrum of physical and functional abnormalities, necessitating a multidisciplinary approach with early and targeted interventions to optimize patient management. Recombinant human growth hormone (rhGH) therapy has demonstrated efficacy in improving body composition, psychomotor development, and appetite in SRS patients, while also reducing the risk of hypoglycemia and enhancing growth velocity (43). Notably, the incidence of adverse effects associated with rhGH therapy is not significantly higher in children diagnosed with SRS compared to those with non-syndromic small for gestational age (94). rhGH treatment is typically initiated following the correction of nutritional deficiencies, with most patients commencing therapy between the ages of 2 to 4 years. Table 13 presents the expert consensus on the off-label use of drugs for pediatric SRS.

Off-label drug use for pediatric anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treatment

AAV is a cluster of systemic disorders characterized by necrotizing inflammation of small vessels, accompanied by the presence of circulating ANCA. This disease spectrum comprises three principal subtypes: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA) (96). AAV predominantly targets small- to medium-sized vessels, resulting in multisystem involvement with a particular predilection for the respiratory tract and renal system. The incidence of AAV exhibits significant variation across different ethnic groups and geographic regions, with global prevalence estimates ranging from 48 to 184 cases per million individuals (97,98). In China, a retrospective analysis utilizing a comprehensive national inpatient database identified a prevalence of 0.25 cases per 1,000 inpatients (99). The estimated prevalence of pediatric AAV is 3.41–4.28 (95% CI: 2.33–6.19) per million children (100). The central pathogenic mechanism involves ANCA-mediated neutrophil activation, which drives disease progression through the formation of neutrophil extracellular traps, activation of the complement cascade, and modulation of the adaptive immune response (101). Immunosuppressive therapy has significantly improved clinical outcomes in AAV patients (102). The therapeutic approach is generally divided into induction therapy (aimed at achieving remission) and maintenance therapy (to prevent relapses) (103). High-quality randomized controlled trials in children with AAV are lacking; therefore, treatment protocols are mainly extrapolated from adult data and expert consensus. For newly diagnosed or relapsing AAV with organ-threatening or life-threatening manifestations, the recommended initial treatment involves glucocorticoids combined with cyclophosphamide or rituximab (103). In cases of non-severe disease, glucocorticoids in combination with mycophenolate, methotrexate, or azathioprine are recommended (103). Table 14 presents the expert consensus on the off-label use of drugs for pediatric AAV.

Off-label drug use for pediatric biliary atresia (BA) treatment

BA represents a severe and life-threatening neonatal disorder characterized by progressive inflammation and fibrosis, leading to partial or complete obliteration of both intrahepatic and extrahepatic bile ducts. Without timely intervention, BA invariably progresses to end-stage liver disease, making it the most common indication for pediatric liver transplantation (105). The incidence of BA exhibits significant geographical and ethnic variation, with reported rates of 1 in 5,000–10,000 live births in China and Japan, compared to 1 in 15,000–20,000 in Europe and North America (106-110). The Kasai portoenterostomy remains the cornerstone of surgical management for BA, significantly improving patient survival and clinical outcomes (105). Postoperative adjuvant therapies are employed to mitigate complications, with glucocorticoids frequently administered to reduce biliary tract edema and inflammation, though current high-quality randomized evidence does not support their efficacy in improving native liver survival or long-term jaundice clearance (111,112). Additionally, ursodeoxycholic acid is routinely utilized for its role in enhancement of bile excretion (111,112). Table 15 presents the expert consensus on the off-label use of drugs for pediatric BA.

Off-label drug use for pediatric neuroblastoma (NB) treatment

NB represents one of the most prevalent extracranial solid malignancies in pediatric populations, constituting approximately 8–10% of all childhood cancers and contributing to nearly 15% of cancer-related mortality in children (114,115). The incidence of NB stands at 10.2 cases per million children under the age of 15 years, making it the most frequently diagnosed cancer during the first year of life (116). This malignancy is characterized by significant biological and clinical heterogeneity, ranging from localized tumors capable of spontaneous regression to aggressive, widely disseminated disease. The International Neuroblastoma Risk Group (INRG) has established a comprehensive classification system that integrates genetic, clinical, and pathological markers to categorize NB into four distinct risk groups: very low risk, low risk, intermediate risk, and high risk (117). Current therapeutic strategies are tailored to patient age and disease stage, encompassing modalities such as surgical resection, chemotherapy, stem cell transplantation, radiation therapy, immunotherapy, isotretinoin and eflornithine (118). Emerging targeted agents such as anaplastic lymphoma kinase (ALK) inhibitors (e.g., lorlatinib), bromodomain and extra-terminal domain (BET) inhibitors, mitogen-activated protein kinase inhibitors (e.g., binimetinib) and histone deacetylase (HDAC) inhibitors have shown promising activity in early-phase clinical trials for relapsed/refractory NB (119). Table 16 presents the expert consensus on the off-label use of drugs for pediatric NB.

Off-label drug use for persistent pulmonary hypertension of the newborn (PPHN) treatment

PPHN is marked by a failure in circulatory adaptation at birth, resulting in the continued presence of elevated pulmonary arterial pressures and reduced pulmonary blood flow during the postnatal period. This condition reflects an inadequate transition from fetal to neonatal circulation, where the pulmonary vascular resistance remains abnormally high, impeding normal blood flow dynamics after birth. This condition occurs in approximately 2 per 1,000 live births and is associated with significant mortality rates, ranging from 7% to 35.7% (124-126). The pathogenesis of PPHN is multifactorial, involving aberrant pulmonary vascular remodeling, endothelial dysfunction, and altered vascular reactivity, all of which contribute to the persistent increase in pulmonary arterial pressure. Therapeutic strategies for PPHN encompass supportive care, ventilation and oxygenation support, pulmonary vasodilator therapy, and other medications (127). Inhaled nitric oxide (iNO), a pulmonary vasodilator, is recognized as the standard of care and has been approved in China for the treatment of PPHN. However, in resource-limited settings where iNO availability is constrained, alternative medications such as sildenafil, bosentan, milrinone, and prostaglandins are utilized (127). Table 17 presents the expert consensus on the off-label use of drugs for PPHN.

Off-label drug use for retinopathy of prematurity (ROP) treatment

ROP, a proliferative retinal vascular disorder predominantly affecting preterm infants with low birth weight, represents a major etiological factor in childhood blindness. Epidemiological studies estimate the pooled prevalence of ROP to range between 21.8–36.5% among preterm infants with a gestational age of less than 32 weeks (130). The disease severity is classified into five distinct stages (stages 1–5), with therapeutic interventions tailored according to both the stage and anatomical location of the pathology (131). The pathogenesis of ROP is multifactorial, with key contributing factors including intermittent hypoxia, oxidative stress, systemic inflammation, dysregulation of vascular endothelial growth factor (VEGF) signaling, retinal vascular immaturity, and oxygen therapy. Current therapeutic modalities primarily include laser photocoagulation and intravitreal anti-VEGF therapy, with the latter demonstrating several advantages over laser treatment, including reduced procedural duration, decreased anesthetic requirements, and minimized visual field defects (132). Long-term safety data for anti-VEGF use in ROP remain limited, particularly regarding neurodevelopmental outcomes. Clinically utilized anti-VEGF agents encompass bevacizumab, aflibercept, conbercept, and ranibizumab, with ranibizumab having received regulatory approval in China for ROP treatment. Table 18 presents the expert consensus on the off-label use of drugs for ROP.

Off-label drug use for systemic juvenile idiopathic arthritis (JIA) treatment

JIA represents a heterogeneous group of systemic disorders of unknown etiology, characterized by the onset of chronic arthritis (persisting for ≥6 weeks) prior to 16 years of age, with exclusion of cases attributable to other known causes. As the most prevalent chronic rheumatic disease in pediatric populations, JIA demonstrates substantial epidemiological variability, with reported prevalence rates ranging from 3.8 to 400 per 100,000 children and annual incidence rates between 0.8 and 23 per 100,000 (137). Systemic JIA (sJIA), a distinct subtype, is characterized by the coexistence of systemic inflammatory features and arthritis, accounting for approximately 10–20% of all JIA cases, with an incidence rate of about 10 per 100,000 (138). Current therapeutic strategies for sJIA encompass a spectrum of pharmacological interventions, including nonsteroidal anti-inflammatory drugs, glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic and targeted synthetic DMARDs (139). Methotrexate, a conventional synthetic DMARD, remains the cornerstone of JIA treatment, while leflunomide serves as an alternative therapeutic option for patients exhibiting methotrexate intolerance or inadequate response. Biologic and targeted synthetic DMARDs are typically employed as second-line therapy in cases of persistent disease activity (140). Recent therapeutic advancements have focused on cytokine-targeted therapies, with particular emphasis on IL-1 inhibitors, IL-6 inhibitors, and tumor necrosis factor-α inhibitors. Registry data show increasing early use of biologic DMARDs and tapering use of conventional DMARDs, especially in severe sJIA (139). Notably, anakinra (an IL-1 receptor antagonist) and tocilizumab (a humanized anti-IL-6 receptor monoclonal antibody) have received regulatory approval for the treatment of sJIA in China. Table 19 presents the expert consensus on the off-label use of drugs for sJIA.

Off-label drug use for pediatric Takayasu arteritis (TAK) treatment

TAK represents a form of large vessel vasculitis characterized by chronic inflammation predominantly affecting the aorta and its primary branches, including the aortic arch, carotid arteries, subclavian arteries, abdominal aorta, and renal arteries. Additionally, involvement of the pulmonary and coronary arteries has been documented. A comprehensive systematic review and meta-analysis recently demonstrated an overall incidence rate of 1.11 cases per million person-years (95% CI: 0.70–1.76) (144). Epidemiological data pertaining to childhood-onset TAK remain limited. A Swedish population-based study reported an annual incidence rate of 0.4 (95% CI: 0–1.1) cases per million individuals for childhood-onset TAK (145). The precise etiological mechanisms underlying TAK remain incompletely elucidated; however, current evidence suggests a strong association with dysregulated immune-mediated processes localized within the arterial wall (146). These aberrant immunological responses are hypothesized to initiate a sequential cascade of pathophysiological alterations, characterized by endothelial cell hyperplasia, neoangiogenesis, fibrotic remodeling, and degradation of elastic laminae. Current therapeutic strategies for childhood-onset TAK are largely extrapolated from adult studies due to a paucity of high-quality evidence. Pediatric data are mostly from small case series and registries, underscoring the need for prospective trials. Standard treatment regimens include corticosteroids in combination with conventional DMARDs (e.g., cyclophosphamide, methotrexate, azathioprine, and mycophenolate mofetil) or biologic agents (e.g., TNFα and IL-6 inhibitors) to mitigate systemic and vascular inflammation (147,148). The combination of corticosteroids with DMARDs constitutes the first-line treatment for TAK. For recurrent and refractory cases, TNFα inhibitors or IL-6R inhibitors may be considered. Table 20 presents the expert consensus on the off-label use of drugs for pediatric TAK.

Off-label drug use for infantile epileptic spasms syndrome (IESS) treatment

IESS, previously referred to as infantile spasms or West syndrome, is an age-specific epileptic disorder that manifests during early infancy, characterized by the presence of epileptic spasms hypsarrhythmia on electroencephalogram (EEG) and developmental regression. There is an incidence rate of 25–60 per 100,000 live births with a prevalence of 15–20 per 100,000 children under the age of 10 years (149). The primary therapeutic objectives for IESS are the cessation of epileptic spasms and the resolution of hypsarrhythmia on EEG. First-line treatments include adrenocorticotropic hormone (ACTH) and oral corticosteroids (150). Vigabatrin, a gamma-aminobutyric acid (GABA) transaminase inhibitor, has demonstrated efficacy in IESS cases associated with tuberous sclerosis complex (151). While evidence for their efficacy remains limited, several antiepileptic drugs, including valproic acid, benzodiazepines, topiramate, and lamotrigine, are also recommended in the management of IESS (152). In China, specific antiepileptic agents such as vigabatrin, valproic acid, and clonazepam have been approved for the treatment of IESS. Early initiation (within 4 weeks of onset) significantly improves developmental outcomes (153). Table 21 presents the expert consensus on the off-label use of drugs for IESS.

Conclusions

This expert consensus was formulated by synthesizing available evidence and integrating key information on clinical practices, evidence levels, and medication safety. The final version was ratified following several rounds of rigorous, iterative expert discussions. This consensus provides evidence support for the treatment of pediatric rare diseases and the management of off-label drug use. It will play a positive role in standardizing the management of such off-label use for pediatric rare diseases, enhancing pharmaceutical care for special populations, and improving the effectiveness and safety of pharmacotherapy. However, this consensus has the following limitations. First, this consensus lacks explicit classification or definitions for levels of evidence and grades of recommendation. Additionally, due to the limitations of available pediatric data, the high-quality evidence we included is relatively scarce. Subsequently, we will update our consensus on a regular basis in light of new evidence. It is important to emphasize that off-label drug use should be avoided when on-label use can yield favorable clinical outcomes. In cases where off-label drug use is deemed necessary, physicians must conduct a comprehensive evaluation of the potential benefits and risks, and adhere to the off-label drug use management protocols of medical institutions. Adverse drug reaction should be monitored and evaluated in patients who received drugs off-label.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-521/prf

Funding: This research was funded by the Scientific Research Fund for Evaluation of Off-label Medication in Rare Diseases of Guangdong Pharmaceutical Association (No. 2025HJB01008).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-521/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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