Safety signals with Nintedanib: Case series exploring the adverse effects of Nintedanib in interstitial lung disease

*Corresponding author: Gopika G Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Safety signals with Nintedanib: Case series exploring the adverse effects of Nintedanib in interstitial lung disease Gopika G 1, *, Sara Kurien Kodiattu 2, Harikrishnan. S 2 and Jacob Jesurun R S 2 1 Pharm D Intern Nazareth College of Pharmacy, Othera, Thiruvalla, Kerala. 2 Department of Pharmacology, Believers Church Medical College Hospital, Thiruvalla, Kerala. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 216-222 Publication history: Received on 04 September 2025; revised on 11 October 2025; accepted on 14 October 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.24.1.0899 Abstract Nintedanib, a Tyrosine Kinase Inhibitor (TKI) with antifibrotic properties, has been approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF), chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype and systemic sclerosisassociated ILD (SSc -ILD). Gastrointestinal (GI) adverse effects and Transaminitis were reported commonly with its use. This case series narrates the clinical experiences of patients treated with Nintedanib and highlights the role of Nintedanib in ILD management while emphasizing the need for careful monitoring to optimize safety and treatment outcomes. Keywords: Nintedanib; Tyrosine kinase Inhibitor; Interstitial Lung disease; Idiopathic Pulmonary Fibrosis; Transient Transaminitis; Hyponatremia 1. Introduction Nintedanib is a small molecule, which is an orally administered Antifibrotic Tyrosine Kinase Inhibitor first approved by the US-FDA in October 2014. Nintedanib was first approved in India by Drugs Controller General of India (DCGI) for SScILD in March 2020, following the positive opinion from CDSCO in March 2020. It is primarily used in the treatment of proliferative diseases such as Idiopathic Pulmonary Fibrosis (IPF), Non-Small Cell Lung Cancer (NSCLC) in addition to systemic sclerosis-associated interstitial lung disease (SSc-ILD). The spectrum of its use has been expanded to currently include chronic Fibrosing Interstitial Lung Disease (ILDs) with a progressive phenotype. Nintedanib is the first approved medication for treating other types of lung disease like ILDs with a progressing status and systemic sclerosis - related lung disease (SSc-ILD) [3]. Nintedanib is a triple kinase inhibitor, which targets fibroblast growth factor receptor (FGFR - involved in cell growth and division), vascular endothelial growth factor receptor (VEGFR - involved in angiogenesis) and platelet-derived growth factor receptor (PDGFR - involved in cell differentiation and migration). Nintedanib was initially designed to treat non-small cell lung cancer; however, it also blocks certain enzymes (tyrosine kinase) involved in cell growth which makes it more beneficial to stop scarring and useful for treating IPF and ILD. Nintedanib with multiple targets exhibits a promising therapeutic action by simultaneously modulating various disease pathways characterised by excessive fibrosis and tumour growth. Nintedanib, competitively binds to the above Tyrosine Kinase Inhibitors which disrupts the signalling pathways responsible for fibroblast proliferation and migration, thereby reducing lung fibrosis [5]. Also, it inhibits kinase activity of Rearranged during Transfection (RET) receptors, Fms-Like Tyrosine kinase 3 (FLT3) receptors for further contribution to its anti-fibrotic activity. Nintedanib which inhibits non-receptor tyrosine kinases Lck, Lyn, and Src, World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 216-222 217 involved in angiogenesis and tumour cell proliferation, where Src inhibition also contributes to its anti-fibrotic effects [4]. Immunosuppressive therapy, supplementary oxygen and supportive care were the mainstay of IPF until 2014 and triple therapy with Prednisolone, Azathioprine and N-acetylcysteine was considered the standard care for IPF [8]. Currently, Nintedanib and Pirfenidone are two anti-fibrotic drugs approved for the treatment of IPF. Nintedanib was expected to show higher risk of bleeding, because it inhibits the VEGF receptors. On the other hand, Nintedanib was preferred for patients with photosensitivity or other existing skin problems [6]. The common adverse drug reactions associated with Nintedanib are GI abnormalities like nausea, diarrhoea, abdominal pain and elevation of liver enzymes (ALT, AST and Bilirubin). Proteinuria and Hypertension were also reported with chronic use of Nintedanib because of its downstream signalling pathway associated with renal dysfunction [7]. Rare adverse effects reported are Bullous Pemphigoid, Ischemic Colitis and Motor Neuropathy. Nintedanib is available in strengths of 150mg and 100mg capsules. Nintedanib induced GI issues and elevation in liver enzymes could be managed with dose modifications or discontinuation of the drug. 2. Case 1 Nintedanib induced elevated liver enzyme A 66-year-old male patient presented with complaints of fever, sore throat, myalgia and cough (whitish sputum) for couple of days and an episode of giddiness (lasting 3-5 sec). The medical history revealed seizure disorder (focal seizures) for 2 years, CVD since 22 years, BPH since 3 years and is currently on Aspirin 150mg once daily therapy and Phenytoin 100mg twice daily. His routine blood investigations showed normal counts, LFT was normal with positive inflammatory markers (CRP-73.3mg/dl). Serum creatinine was normal and Urea was elevated (56 mg/dl). NIV (BIPAP) was initiated in view of saturation drop. Covid and H1N1 screening were done which came back positive for Covid –19. So, he was shifted to the Isolation ICU. He was treated with a course of Antiviral - Inj.Remdesivir 100mg/vial once daily and Inj. Ceftriaxone 1g twice daily and Azithromycin 500mg once daily. In view of Haemoglobin drop, Stool occult blood was sent and it was positive 1+ following which Pantoprazole infusion was started. ABG showed Respiratory Alkalosis and HRCT revealed right sided lung involvement and increasing CRP trend with 235mg/dl which led to the addition of Nintedanib 150mg once daily. After taking the drug, his LFT showed abnormality, which raised the suspicion of Nintedanib being the offending drug in the absence of other probable causes. After Nintedanib discontinuation, LFT showed a declining trend. At the time of discharge, he was stable and initiation of diabetic diet was recommended. After 19 days, his blood counts were repeated which demonstrated normal levels. Table 1 Liver enzymes before and after stopping Nintedanib. LIVER FUNCTION TEST AST (SGOT ALT (SGPT) ALKALINE PHOSPHATASE (ALP) ALBUMIN BEFORE STARTING THE DRUG 50U/L 51U/L 108U/L 4.28g/dl AFTER STARTING THE DRUG 444U/L 399U/L 124U/L 3.03g/dl 3rd DAY AFTER STOPPING THE DRUG 92U/L 149U/L 102U/L 3.4g/dl NORMAL RANGE 10 - 40 U/L 10 - 40 U/L 44 -147 IU/L 3.55.0g/dl 3. Case no :2 Nintedanib induced transaminitis A 62-year-old female patient with medical history of Dermatomyositis with Interstitial Lung Disease, currently on Inj. Rituximab 3g doses and Nintedanib 100mg twice daily, presented to the Emergency department with complaints of breathlessness, persistent wet cough and orthopnea. Upon evaluation, she had significant hypoxemia with only 40% saturation, Blood pressure ranging 170/90mmHg and a heart rate of 90 beats per minute. She also has a history of Hypertension and Dyslipidemia for 5 years and is being managed with a combination of Tab. Hydrochlorothiazide + Telmisartan (12.5/40mg) once daily and Rosuvastatin 10mg once daily. Routine investigations showed elevated white blood cell count of 14,600 with a drop of platelet count to 0.59. In view of worsening Chest X ray (infection in both lungs and lower corner of right lung was not visible) and raised inflammatory markers (CRP 56.9 ascending from 22.1), sepsis was considered a possibility and antibiotics Inj. Ceftriaxone substituted with Inj. Meropenem 500mg twice daily along with Inj. Dexamethasone 4mg thrice daily. Neurology opinion was sought with the anticipation of metabolic encephalopathy, workup on the same revealed hyponatremia and hyperammonemia and on further evaluation, showed World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 216-222 218 altered parenchymal changes. During hospital stay, she developed painful skin lesions over the lip and tongue and was started on Fluconazole 150mg once daily. Pulmonology consultation was sought in view of ammonia elevation following which Lactulose enema and Syrup Sucralfate were added. There are no other potential factors that may have contributed to transaminitis. Hence the causal drug was withheld. After discontinuation of the drug, Liver enzymes became normalized. Table 2 Liver enzymes before and after stopping Nintedanib LIVER FUNCTION TEST ALBUMIN AST ALT ALKALINE PHOSPHATASE BEFORE STARTING DRUG 3.89 26 28 17 AFTER STARTING DRUG 2.82 164 566 178 AFTER STOPING DRUG 2.53 58 95 121 NORMAL RANGE 3.5-5.0g/dl 10 - 40 U/L 10 - 40 U/L 44-147IU/L 4. Case no 3: nintedanib induced transient transaminitis and hyperphosphatemia A 58-year-old female patient came with complaints of breathlessness, vomiting, productive cough (yellowish sputum) for a couple of days. Patient is a diagnosed case of Interstitial lung disease in the last 2 years, Rheumatoid arthritis for 15 years and Type II DM since a year and is on a combination of Sitagliptin - Metformin 50/500mg tablet twice daily, Methylprednisolone 4mg twice daily and Nintedanib 100mg twice daily. Routine blood investigations showed elevated Phosphorus level (6.26g/mol), and patient was consulted in view of newly developed AKI. It was considered that hyperphosphatemia is most probably due to Nintedanib. Following discontinuation of Nintedanib, serial monitoring of blood investigations revealed decreasing trend of CRP and Phosphate. Patient was symptomatically better and discharged with suitable medications. Table 3 Phosphate level before and after stopping Nintedanib PHOSPHATE LEVELS AFTER STARTING THE DRUG 6.26 AFTER STOPPING THE DRUG 2.74 NORMAL RANGE 2.5-4.5mg/dl After 2 days, Nintedanib was restarted with dose modification as 150mg once daily and was advised to continue for 2 months. After 4 months, Patient came with similar complaints to the Emergency department. On examination, patient was desaturated with SPO2 90% and her blood investigation showed CRP 475.7mg/dl, with a total count of 8100. She was started with a course of AntibioticsInj. Meropenem 1g once daily and Azithromycin 500mg twice daily. During hospital stay, LFT showed elevated liver enzymes, following which Nintedanib was suspected and the causal drug was stopped. Liver enzymes improved after stopping the drug. She was followed up later and blood reports, liver enzymes and phosphate were found to be within normal limits. Table 4 Liver enzymes before and after stopping Nintedanib. LIVER ENZYMES SGOT(AST) SGPT(ALT) BEFORE STARTING THE DRUG 17 10 AFTER STARTING THE DRUG 92 60 AFTER STOPPING THE DRUG 25 6 NORMAL RANGE 10-40U/L 10-40U/L World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 216-222 219 5. Case no 4: Nintedanib induced hyponatremia A 63-year-old male patient with a history of oesophageal cancer since 4 years managed with chemoradiation, Type II DM since a year (currently on combination of Vildagliptin + Metformin - 50/500 mg twice daily) presented to the Emergency department with complaints of vomiting, generalised weakness, shortness of breath for the past 5 days. On examination, he was conscious and mild pedal oedema with bilateral crackles in the lungs were noticed. HRCT chest showed widespread hazy areas in both lungs, with some scarring near the outer edges. The patient was started on Nintedanib 150mg twice daily. Routine blood investigations showed Hyponatremia with Sodium level of 109 mEq. In absence of other probable causes, Nintedanib dose was reduced to make 100mg twice daily. Other medications administered were IV Antibiotics, Doxycycline 100mg once daily and Oseltamivir 75mg once daily. Sodium values were repeated showing Hyponatremia with Sodium level 111mEq. The association between the Nintedanib dose reduction and development of hyponatremia, and in consideration of patient’s clinical presentation and investigations, Nintedanib induced Hyponatremia was suspected. Following the discontinuation of Nintedanib, Sodium level improved up. He was advised with discharge medications and diabetic diet instructions. Table 5 Sodium level before and after stopping Nintedanib SODIUM LEVEL DURING HOSPITAL STAY After starting Nintedanib 109mEq, 111mEq After stopping Nintedanib 114mEq ---118mEq---122mEq---126mEq Normal Levels 135-145mEq 6. Case no 5: Nintedanib induced gi disorder A 76-year-old male patient came with Interstitial Lung Disease diagnosis (Fibrotic Non - specific Interstitial Pneumonia associated with anti-Jo-1 antibody Positive) since a year, Type II DM and Hypertension since 30 years, is currently being managed with Methylprednisolone 4 mg once daily, Basal insulin 10 units once daily and Cilnidipine 10mg once daily. He presented to ER with complaints of cough and breathlessness for a couple of days (progressive and productive with scanty whitish sputum) and history of fever 4 days back. He also had complaints of persistent diarrhoea characterized by 2-3 episodes per day, with features of blood tinged stools, despite use of anti-diarrheal medications like Loperamide and showed signs of dehydration and sudden weight loss (from 82.5 to 76kg). Routine lab investigations at the time of admission revealed a total leucocyte count of 7600, Hb 12.7g/dl, Platelet 1.98 and CRP 19.9mg/L. Chest X ray showed bilateral infiltrates and ECG showed sinus tachycardia. In view of ILD, patient was started on Nintedanib 100mg once daily. Other medications administered were Hydrocortisone 6th hourly and Oseltamivir 75mg once daily. Pulmonology team asked to continue the same line of treatment with the addition of MDI Formoterol fumarate and Budesonide 400mcg 2 puffs twice daily. In view of symptomatic improvement except diarrhoea, Nintedanib discontinuation was opted considering other co-morbidities in the patient. On discharge, he was hemodynamically stable; Systemic evaluation showed resolving bilateral wheeze and full symptomatic improvement. During his subsequent appointment for therapy, the patient had no GI issues. 7. Discussion Nintedanib has shown clear benefit in IPF and SSc-ILD. All the above cases are a testament to the efficacy of the drug. However, routine use of Nintedanib requires monitoring for both GI and Hepatic side effects. As a pregnancy category D drug, Nintedanib is contraindicated in pregnancy and is also to be avoided in patients with hepatic impairment (Child -Pugh class A). In our case series, multiple patients experienced GI abnormality like diarrhoea and liver enzyme abnormalities like transient transaminitis with the use of Nintedanib even while on therapy with standard doses for the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. These findings resemble that of study conducted by Kevin. R et. al [14] which point out the safety profile of Nintedanib: patients in the Nintedanib group with 150mg twice daily required dose reduction and discontinuation of therapy. No cases of proteinuria, hypertension or other serious adverse events have been reported in the passive surveillance. The exact mechanism behind the Nintedanib induced Liver injury is not completely understood. It is believed that, most drugs are metabolised in liver and its metabolic products induce oxidative stress that damage the liver which causes cholestasis and results in abnormalities in liver enzymes and bilirubin level. Elevation in liver enzymes (AST, ALT) and bilirubin (including drug induced liver injury) may occur in patients treated with Nintedanib. LFT should be World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 216-222 220 recommended prior to the initiation of treatment and during the first three months of treatment [10]. It is recommended that Nintedanib therapy is interrupted or dose reduced in patients where elevated liver enzymes occur with signs of liver injury. According to evidence available, liver enzymes and bilirubin elevation in patients treated with Nintedanib were reversible through cessation of therapy or dose reduction[11,13]. Liver enzyme abnormalities of each patient in this series (before and after the stoppage of Nintedanib) have been highlighted in tables. In our cases, patients using the Nintedanib therapy for IPF in the hospital stay, or OPD basis do show elevated liver enzymes forcing the discontinuation of the drug despite their efficacy. These resemble the study conducted by Adhithya et.al, which emphasize the discontinuation of Nintedanib after liver enzyme abnormality and LFT monitoring during treatment [12]. In addition to Liver Function Tests (Bilirubin, AST, ALT), Sodium and Phosphate levels are recommended monitoring before the initiation of the drug and at regular intervals, especially during the first 3 months of treatment. These studies point out that individualised treatment including dosage adjustments and tolerability to adverse effects should be done on a case-to-case basis [10]. In the study conducted by Lasky A Joseph et.al with Global Pharmacovigilance data, collected exposure to Nintedanib was estimated at 60,107 patient-years where diarrhoea is the most common adverse effect occurring at 30.2% rate[10]. Nausea, diarrhoea and liver dysfunction were the most common adverse effects of Nintedanib for IPF treatment. According to the INPULSIS trials conducted in 2014 and 2015, diarrhoea was reported the most common adverse effect and affected over 62.4% patients with mild to moderate cases and 55.3% patients had to use Anti-diarrheal medications (Loperamide 2mg) while another 4.4% stopped the medication due to diarrhoea [9].The exact mechanism of Nintedanib causing nausea and diarrhoea is not understood but it is believed to be the inhibition of VEGF receptors which leads to structural changes of the bowel lining which affects its function and motility (VEGF and VEGFR are mostly seen in endocrine glands, stomach and intestines). GI symptoms usually occur after few weeks of initiation of Nintedanib [15]. Patients also reported that they tolerated small doses only. In certain situations, patients needed to be treated with steroids for rapid resolution of symptoms in case of acute worsening of respiratory symptoms and development of autoimmune flare in ILD [16]. In one of our patients, who was already receiving Methylprednisolone for the management of ILD, was advised to continue steroid therapy with tapering as utilised for rapid resolution of symptoms. Most of the cases, there is a symptomatic improvement in GI symptoms after discontinuation of Nintedanib. Diarrhoea is most common with 66.9% occurrence with nausea, vomiting, abdominal pain, decreased appetite, weight loss as other adverse effects. It reminds us the need for close monitoring and dosage modifications in therapy for better patient outcomes [14]. The risk of bleeding associated with Nintedanib is increased due to its mechanism of VEGFR inhibition and is not dose dependent. However, no instances of Nintedanib induced bleeding or any cardiovascular adverse events were observed among our patients. According to our study, Cases 1,2 and 4 were all Type B reactions - non dose dependent and unpredictable. So, termination of Nintedanib was necessary to decrease the severity of diagnosis which emphasizes that it is reversible. In these, the causality was found to be “PROBABLE” according to World Health Organization –Uppsala Monitoring Centre (WHO-UMC) assessment scale and Naranjo Assessment Scale. Applying the Modified Hartwig and Siegel Severity Assessment Scale, these cases typically fall into the moderate category (Level 3). Case no 3 demonstrated similar features as Case no 1, however it differed in the WHO-UMC causality scale wherein it measured as “CERTAIN” due to rechallenge of the drug. Case no 5 demonstrated mild to moderate severity (Level 2) according to the Modified Hartwig and Siegel scale, consistent with the severity levels observed in the other reported cases. In recent years, antifibrotic therapies have been in common use. Nintedanib is the only antifibrotic drug currently recommended for the treatment of IPF; Pirfenidone is less consistent. Our observations in each of these cases emphasize the importance of individualized treatment plans for patients, managing drug related adverse events alongside complex co-morbidities. Abbreviations • IPD - Interstitial pulmonary disease • ILD - Interstitial Lung disease • PF - Pulmonary fibrosis • ALTAlanine transaminase • AST – Aspartate transaminase • LDH - Lactate dehydrogenase World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 216-222 221 • LFT - Liver Function Test • CRPC-Reactive Protein • GIGastrointestinal • ADR - Adverse Drug Reaction • ER - Emergency department • OPD - Outpatient department • USG - Ultrasound sonography • HRCT - High Resolution Computed Tomography • RDP - Random Donor Platelet 8. Conclusion In conclusion, Nintedanib is a valuable drug for the treatment of pulmonary fibrosis, as it helps to slow disease progression. However, regular monitoring is crucial for delivering efficacious treatment and to achieve disease remission for better long-term outcomes while avoiding toxic side effects. Further studies are necessary to assess the safety of Nintedanib in clinical practice. Such studies may help evaluate both GI toxicity and hepatotoxicity in patients with IPF who receive Nintedanib and to better understand the long-term safety profile of the drug [11]. Compliance with ethical standards Acknowledgments The authors would like to express heartfelt gratitude and regards to the ADR Monitoring Centre at Believers Church Medical College Hospital, Thiruvalla, for their kind support in reporting this ADR. Disclosure of conflict of interest The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. Statement of informed consent The authors certify that, they have obtained all appropriate patient consent documents. In the documents, the patient consented for her clinical information to be reported in the journal. 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