nintedanib
Sources réglementaires consultées
Indications approuvées
- Chez l’adulte, fibrose pulmonaire idiopathique, autres pneumopathies interstitielles fibrosantes chroniques à phénotype progressif et pneumopathie interstitielle associée à la sclérodermie systémique.
Contre-indications
Absolues
- Grossesse.
- Hypersensibilité au nintédanib ou à ses excipients.
Mises en garde cliniques
- Mise en garde majeure · Peut provoquer une atteinte hépatique, parfois mortelle. Contrôler ALT, AST et bilirubine avant traitement, régulièrement pendant les 3 premiers mois puis périodiquement ; ajuster ou arrêter selon les résultats et les symptômes. — DailyMed, nintedanib set_id 9925b305-c1fb-43b6-a5fd-e03f14f28e6c
- Mise en garde majeure · La diarrhée, les nausées et les vomissements peuvent être sévères. Commencer hydratation et traitement antidiarrhéique ou antiémétique dès les premiers signes ; réduire ou suspendre s’ils persistent et arrêter en cas de symptômes sévères persistants malgré les soins de support. — DailyMed, nintedanib set_id 9925b305-c1fb-43b6-a5fd-e03f14f28e6c
- Mise en garde majeure · Surveiller hémorragie, événements thromboemboliques artériels, perforation gastro-intestinale, atteinte rénale ou protéinurie et risque d’anévrisme ou de dissection artérielle. Évaluer soigneusement le rapport bénéfice-risque avec anticoagulation complète, corticoïdes ou AINS. — CIMA/AEMPS, ficha técnica NINTEDANIB CINFA 90483
Interactions médicamenteuses
- ModéréeInhibiteurs de la P-gp et du CYP3A4
Mécanisme: Ils peuvent augmenter l’exposition au nintédanib.
Recommandation: Surveiller étroitement la tolérance et les effets indésirables ; réduire ou suspendre si nécessaire.
DailyMed, nintedanib set_id 9925b305-c1fb-43b6-a5fd-e03f14f28e6chttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9925b305-c1fb-43b6-a5fd-e03f14f28e6c
- SévèreInducteurs de la P-gp et du CYP3A4
Mécanisme: Ils réduisent l’exposition et peuvent diminuer l’efficacité.
Recommandation: Éviter l’association, y compris le millepertuis.
DailyMed, nintedanib set_id 9925b305-c1fb-43b6-a5fd-e03f14f28e6chttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9925b305-c1fb-43b6-a5fd-e03f14f28e6c
- SévèreAnticoagulants à dose thérapeutique
Mécanisme: L’effet antiangiogénique peut augmenter le risque hémorragique.
Recommandation: Surveiller étroitement les signes de saignement et réévaluer l’association selon le risque individuel.
DailyMed, nintedanib set_id 9925b305-c1fb-43b6-a5fd-e03f14f28e6chttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9925b305-c1fb-43b6-a5fd-e03f14f28e6c
Effets indésirables
Communs (≥1%)
diarrhée · nausées · douleur abdominale · vomissements · diminution de l’appétit · perte de poids · élévation des enzymes hépatiques
Grossesse et allaitement
Contre-indiqué pendant la grossesse et susceptible de provoquer une toxicité embryofœtale. Vérifier la grossesse et utiliser une contraception hautement efficace dès l’initiation, pendant le traitement et pendant au moins 3 mois après ; en cas de vomissements ou diarrhée, utiliser une méthode alternative non orale. Ne pas allaiter pendant le traitement.
Bibliographie récente (PubMed)
Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results:1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed de
Interstitial lung disease (ILD) consists of a group of pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma associated with progressive dyspnea that frequently results in end-stage respiratory failure. In the US, ILD affects approximately 650 000 people and causes approximately 25 000 to 30 000 deaths per year. The most common forms of ILD are idiopathic pulmonary fibrosis (IPF), which accounts for approximately one-third of all cases of ILD, hypersensitivity pneumonitis, accounting for 15% of ILD cases, and connective tissue disease (CTD), accounting for 25% of ILD cases. ILD typically presents with dyspnea on exertion. Approximately 30% of patients with ILD report cough. Thoracic computed tomography is approximately 91% sensitive and 71% specific for diagnosing subtypes of ILDs such as IPF. Physiologic assessment provides important prognostic information. A 5% decline in forced vital capacity (FVC) over 12 months is associated with an approximately 2-fold increase in mortality compared with no change in FVC. Antifibrotic therapy with nintedanib or pirfenidone slows annual FVC decline by approximately 44% to 57% in individuals with IPF, scleroderma associated ILD, and in those with progressive pulmonary fibrosis of any cause. For connective tissue disease-associated ILD, immunomodulatory therapy, such as tocilizumab, rituximab, and mycophenolate mofetil, may slow decline or even improve FVC at 12-month follow-up. Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in individuals with dyspnea. Oxygen reduces symptoms and improves quality of life in individuals with ILD who desaturate below 88% on a 6-minute walk test. Lung transplant may improve symptoms and resolve respiratory failure in patients with end-stage ILD. After lung transplant, patients with ILD have a median survival of 5.2 to 6.7 years compared with a median survival of less than 2 years in patients with advanced ILD who do not under
Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilized lung function over a period of 12 weeks. In this phase 3, double-blind trial, we randomly assigned patients with idiopathic pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background antifibrotic therapy (nintedanib or pirfenidone vs. none). The primary end point was the absolute change from baseline in forced vital capacity (FVC), measured in milliliters, at week 52. A total of 1177 patients underwent randomization, of whom 77.7% were taking nintedanib or pirfenidone at enrollment. Adjusted mean changes in FVC at week 52 were -114.7 ml (95% confidence interval [CI], -141.8 to -87.5) in the nerandomilast 18-mg group, -138.6 ml (95% CI, -165.6 to -111.6) in the nerandomilast 9-mg group, and -183.5 ml (95% CI, -210.9 to -156.1) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 68.8 ml (95% CI, 30.3 to 107.4; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 44.9 ml (95% CI, 6.4 to 83.3; P = 0.02). The most frequent adverse event in the nerandomilast groups was diarrhea, reported in 41.3% of the 18-mg group and 31.1% of the 9-mg group, as compared with 16.0% in the placebo group. Serious adverse events were balanced across trial groups. In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-IPF ClinicalTrials.gov number, NCT05321069.).
Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory properties. Nerandomilast has been shown to slow the progression of idiopathic pulmonary fibrosis, but an assessment of its effects in other types of progressive pulmonary fibrosis is needed. In a phase 3, double-blind trial, we randomly assigned patients with progressive pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background therapy (nintedanib vs. none) and fibrotic pattern on high-resolution computed tomography (usual interstitial pneumonia-like pattern vs. other patterns). The primary end point was the absolute change from baseline in the forced vital capacity (FVC), measured in milliliters, at week 52. A total of 1176 patients received at least one dose of nerandomilast or placebo, of whom 43.5% were taking background nintedanib therapy at baseline. The adjusted mean change in the FVC at week 52 was -98.6 ml (95% confidence interval [CI], -123.7 to -73.4) in the nerandomilast 18-mg group, -84.6 ml (95% CI, -109.6 to -59.7) in the nerandomilast 9-mg group, and -165.8 ml (95% CI, -190.5 to -141.0) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 67.2 ml (95% CI, 31.9 to 102.5; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 81.1 ml (95% CI, 46.0 to 116.3; P<0.001). The most frequent adverse event was diarrhea, reported in 36.6% of the patients in the nerandomilast 18-mg group, 29.5% of those in the nerandomilast 9-mg group, and 24.7% of those in the placebo group. Serious adverse events occurred in similar percentages of patients in the trial groups. In patients with progressive pulmonary fibrosis, treatment with nerandomilast led to a smaller decline in the FVC than placebo ove
Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by excessive deposition of extracellular matrix (ECM) and abnormal fibroblast proliferation, which is mainly caused by air pollution, smoking, aging, occupational exposure, environmental pollutants exposure, and microbial infections. Although antifibrotic agents such as pirfenidone and nintedanib, approved by the United States (US) Food and Drug Administration (FDA), can slow the decline in lung function and disease progression, their side effects and delivery inefficiency limit the overall prognosis of PF. Therefore, there is an urgent need to develop effective therapeutic targets and delivery approaches for PF in clinical settings. This review provides an overview of the pathogenic mechanisms, therapeutic drug targeting signaling pathways, and promising drug delivery strategies for treating PF.