Nintedanib

539.62482

539.62

1592732-453-0

G6HRD2P839

C62765

L01XE3|L01XE|L - Antineoplastic and immunomodulating agents

94.2

3.3

1.3±0.1 g/cm3

305C

742.199°C at 760 mmHg

402.7±32.9 °C

1.658

In water, 9.66 mg/L at 25 deg C (est)

Store at 25 deg C (77 deg F); excursions permitted to 15 deg to 30 deg C (59 deg to 86 deg F). Protect from exposure to high humidity and avoid excessive heat. If repackaged, use USP tight container.

2.18X10-18 mm Hg at 25 deg C (est)

Henry's Law contant = 2.42X10-24 atm-cu m/mol at 25 °C (est)|Hydroxyl radical reaction rate constant = 2.39X10-10 cu cm/molecule-sec at 25 °C (est)|Ozone radical reaction rate constant = 2.53X10-16 cu cm/molecule-sec at 25 °C (est)

P201, P202, P260, P264, P270, P280, P281, P301+P310, P302+P352, P305+P351+P338, P308+P313, P310, P314, P321, P330, P332+P313, P362, P405, P501

H301

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including nintedanib esylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Nintedanib esylate/

|Danger|H301 (80.85%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P264, P270, P280, P281, P301+P310, P302+P352, P305+P351+P338, P308+P313, P310, P314, P321, P330, P332+P313, P362, P405, and P501|Aggregated GHS information provided by 47 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Experience with nintedanib overdose is limited, but patients who inadvertently received higher-than-intended doses during initial trials experienced adverse effects consistent with the known safety profile of nintedanib, for example elevated liver enzymes and significant gastrointestinal effects. There are no specific guidelines for the treatment of nintedanib overdose - in this case, therapy should be interrupted and general supportive measures employed as indicated.|IDENTIFICATION AND USE: Nintedanib is an antineoplastic agents and enzyme inhibitor used for the treatment of idiopathic pulmonary fibrosis (IPF) and cancer. HUMAN EXPOSURE AND TOXICITY: Adverse effects associated with nintedanib may include diarrhea, nausea, abdominal pain, elevated concentrations of hepatic enzymes, vomiting, decreased appetite, decreased weight, headache, and hypertension. Arterial thromboembolic events such as myocardial infarction have been reported in patients receiving nintedanib. In one case, a 64-year-old man with IPF had nintedanib added to his ongoing pirfenidone therapy. He developed dyspnea after 65 days and presented with hypoxemia after 68 days. He was diagnosed with an acute exacerbation of IPF. Nintedanib was temporarily discontinued and the acute exacerbation was successfully managed with intensive treatment. Nintedanib was safely and successfully restarted after treatment of the acute exacerbation. Based on findings from animal studies and its mechanism of action, the drug can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential. ANIMAL STUDIES: Two-year oral carcinogenicity studies of nintedanib in rats and mice have not revealed any evidence of carcinogenic potential. A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility. In female rats, nintedanib reduced fertility, including increases in resorption and post-implantation loss, at exposures below the maximum recommended human dose (MHRD) of 150 mg b.i.d. based on AUC. A decrease in the number and size of corpora lutea in the ovaries was observed in chronic toxicity studies in rats and mice. Nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits at less than and approximately 5 times the MRHD in adults. Nintedanib was negative for genotoxicity in the in vitro bacterial reverse mutation assay, the mouse lymphoma assay, and the in vivo rat micronucleus assay.

In large randomized controlled trials, serum enzyme elevations occurred in up to 14% of patients receiving nintedanib compared to 3% of controls. Aminotransferase values above 3 times the upper limit of normal (ULN) occurred in only 3% to 5% of patients (compared to

In a multiple dose study in Japanese patients with idiopathic pulmonary fibrosis (IPF), addition of nintedanib to ongoing pirfenidone therapy resulted in a 41 and 32% decrease in nintedanib peak plasma concentrations and area under the concentration-time curve (AUC), respectively, compared with nintedanib alone. Concomitant use of nintedanib and pirfenidone did not have an effect on the pharmacokinetics of pirfenidone. In this study, nausea and vomiting were reported more frequently with concomitant nintedanib and pirfenidone therapy compared with nintedanib alone; all adverse effects reported in the study were mild or moderate in severity.|Nintedanib may increase the risk of bleeding. The manufacturer states that patients receiving full-dose anticoagulation therapy should be monitored closely for bleeding; dosage adjustment of the anticoagulant may be necessary.|Because the aqueous solubility of nintedanib is pH dependent (i.e., increased solubility at pH less than 3), drugs that increase gastric pH may potentially affect the bioavailability of nintedanib. However, concomitant administration of proton-pump inhibitors or H2-receptor antagonists in clinical studies did not affect trough concentrations of nintedanib.|Concomitant oral administration of nintedanib and rifampin (an inducer of P-gp and CYP3A4) decreased peak plasma concentrations and systemic exposure of nintedanib by about 60 and 50%, respectively.|For more Interactions (Complete) data for Nintedanib (8 total), please visit the HSDB record page.

Nintedanib is predominantly eliminated via biliary/fecal excretion (>90%). In a PK study performed in patients with hepatic impairment (Child Pugh A, Child Pugh B), exposure to nintedanib was increased. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of Ofev is 100 mg twice daily. Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Ofev is not recommended.|Based on findings from animal studies and its mechanism of action, Ofev can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential.|Nintedanib may increase the risk of GI perforation based on its mechanism of action. GI perforation was reported in 0.3% of nintedanib-treated patients in clinical studies. Nintedanib should be used with caution in patients who have had recent abdominal surgery. In patients with risk factors for GI perforation, nintedanib should be used only if the potential benefit outweighs the risk.|Because nintedanib inhibits vascular endothelial growth factor receptor (VEGFR), the risk of bleeding may be increased. Bleeding events were reported in 10% of patients receiving nintedanib compared with 7% of patients receiving placebo. Nintedanib should be used in patients with risk factors for bleeding only if the potential benefit outweighs the risk.|For more Populations at Special Risk (Complete) data for Nintedanib (6 total), please visit the HSDB record page.

Plasma protein binding of nintedanib is high, with a bound fraction of 97.8%. Albumin is thought to be the major binding protein.

In the US, nintedanib is indicated for the treatment of idiopathic pulmonary fibrosis (IPF) and to slow declining pulmonary function in patients with systemic sclerosis-associated interstitial lung disease. In the EU, nintedanib is indicated in combination with docetaxel for the treatment of adult patients with metastatic, locally advanced, or locally recurrent non-small cell lung cancer of adenocarcinoma histology who have already tried first-line therapy.|Vargatef is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first line chemotherapy.|Ofev is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF).|Treatment of fibrosing Interstitial Lung Diseases (ILD)|Treatment of lung carcinoma (small cell and non-small cell carcinoma), Treatment of mesothelioma|Treatment of systemic sclerosis

Nintedanib is an orally available tyrosine kinase receptor antagonist that inhibits collagen formation and is used to treat idiopathic pulmonary fibrosis. Elevations in serum enzyme levels during nintedanib therapy are not uncommon, but it has yet to be implicated in cases of clinically apparent liver injury with jaundice.

Pulmonary Fibrosis Agents

Antineoplastic Agents; Enzyme Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Nintedanib is included in the database.|Ofev is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). /Included in US product label/|/EXPL THER/ The treatment of advanced non-small cell lung cancer (NSCLC) is currently driven by the detection of targetable oncogenic drivers, i.e. epidermal growth factor receptor, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, etc. Those patients who are wildtype for known and valuable oncogenes can receive standard chemotherapy as first-line treatment, with the possibility of adding bevacizumab. With regard to second-line treatment, nintedanib can improve the efficacy of docetaxel. Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors. The usefulness of nintedanib as an anticancer agent for NSCLC has been proved by both preclinical and clinical phase I and II trials; however, its approval for the use in clinical practice has been possible because of the positive results of the LUME-Lung 1 trial (nintedanib + docetaxel versus docetaxel alone) in terms of progression-free survival and overall survival, and a manageable tolerability profile. Therefore, the good results seen in the clinical trials with nintedanib in the second-line setting for NSCLC patients with adenocarcinoma subtype are encouraging enough to recommend it in clinical practice.|For more Therapeutic Uses (Complete) data for Nintedanib (6 total), please visit the HSDB record page.

Based on animal findings, nintedanib may cause fetal harm if administered to pregnant women. Embryofetal toxicity and teratogenicity have been demonstrated in rats and rabbits given nintedanib dosages less than and approximately 5 times the maximum recommended human dose. Teratogenic effects included missing or additional major blood vessels, skeletal abnormalities, or missing urogenital organs.Women of childbearing potential should use effective contraception while receiving nintedanib and for at least 3 months after the drug is discontinued.If nintedanib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.|Safety and efficacy of nintedanib have not been established in pediatric patients.|Nintedanib and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because of the potential for serious adverse reactions to nintedanib in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.|Adverse effects reported in 5% or more of patients receiving nintedanib and at an incidence greater than with placebo include diarrhea, nausea, abdominal pain, elevated concentrations of hepatic enzymes (e.g., ALT, AST, alkaline phosphatase), vomiting, decreased appetite, decreased weight, headache, and hypertension.|For more Drug Warnings (Complete) data for Nintedanib (16 total), please visit the HSDB record page.

Nintedanib is a small molecule kinase inhibitor that inhibits upstream kinase activity to ultimately inhibit lung fibroblast proliferation and migration, as well as signalling pathways that promote the proliferation and survival of endothelial and perivascular cells in tumour tissues. Nintedanib poses a risk of drug-induced liver injury, especially within the first three months of therapy. Liver function tests should be conducted at baseline prior to beginning therapy, at regular intervals for the first three months of therapy, and as indicated thereafter in patients exhibiting symptoms of hepatic injury such as jaundice or right upper quadrant pain. It is not recommended to be used in patients with pre-existing moderate to severe hepatic impairment (Child Pugh class B or C).

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

The absolute bioavailability of nintedanib is low at approximately 4.7%, likely owing to substantial first-pass metabolism and the effects of p-glycoprotein (P-gp) transporters. T_max following oral administration is reached after approximately 2 hours in fasted patients and approximately 4 hours in fed patients, regardless of the food consumed. Administration of nintedanib following a high-fat, high-calorie meal resulted in an increase in C_max by approximately 15% and an increase in AUC by approximately 20%. Age, body weight, and smoking status have been found to alter exposure to nintedanib, but these effects are not significant enough to warrant dose alterations.|Nintedanib is eliminated primarily via fecal and biliary excretion, with 93.4% of radio labelled nintedanib found in feces within 120 hours following administration. Renal clearance accounts for a small portion of nintedanib's elimination, approximately 0.65% of the total dose, and excretion of unchanged nintedanib 48 hours after oral and intravenous doses was 0.05% and 1.4%, respectively.|Nintedanib appears to follow biphasic disposition kinetics - the observed volume of distribution following intravenous administration is 1050 L, indicating extensive distribution into peripheral tissues. In rats, nintedanib was shown to rapidly and homogeneously distribute into peripheral tissues with the exception of the CNS, suggestive of an inability of nintedanib to cross the blood-brain barrier.|Nintedanib is has a high total plasma clearance of approximately 1390 mL/min and a renal clearance of 20 mL/min.|/MILK/ Nintedanib and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk.|Pharmacokinetics (PK) of nintedanib after oral single- and multiple-doses and intravenous (i.v.) administration were assessed using three datasets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of four studies that enrolled a total of 113 healthy volunteers; (3) a pooled data analysis of four studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean: 1390 mL/min) and a high volume of distribution at steady state (Vss = 1050 L). Urinary excretion of i.v. nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after i.v. administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to i.v. dosing (4-hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first-pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice-daily dosing. Nintedanib's PK was time-independent; accumulation after repeated administration was negligible.|Nintedanib follows bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution which was larger than total body volume (Vss: 1050 L) was observed. The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.|After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median tmax fasted: 2.00 hours; fed: 3.98 hours), irrespective of the food type.|For more Absorption, Distribution and Excretion (Complete) data for Nintedanib (10 total), please visit the HSDB record page.

Nintedanib is predominantly metabolized via hydrolytic cleavage by esterases to its principle metabolite, BIBF 1202, which then undergoes glucuronidation via UGT enzymes in the intestines and liver (specifically UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10) to form BIBF 1202 glucuronide. The CYP450 enzyme system plays a minor role in nintedanib metabolism, with CYP3A4 believed to be the main contributor - the major CYP-dependent metabolite of nintedanib, a demethylated metabolite termed BIBF 1053, could not be detected in plasma during pharmacokinetic studies and was found only in small quantities in the feces (approximately 4% of total dose). CYP-dependent metabolism of nintedanib accounts for roughly 5% of total drug metabolism, as opposed to 25% for esterase cleavage. Other minor metabolites, M7 and M8, are found in very small quantities in the urine (0.03% and 0.01%, respectively), though their origin and relevance is currently unclear.|The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.

The terminal elimination half-life of nintedanib is approximately 10-15 hours. In patients with idiopathic pulmonary fibrosis, the effective half-life of nintedanib has been estimated to be approximately 9.5 hours.|The effective half-life of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) was 9.5 hours (gCV 31.9%).|The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), were studied in healthy male volunteers (n = 8) who had received a single oral dose of 100 mg (14)C-radiolabelled BIBF 1120 administered as solution. BIBF 1120 /had a/ gMean /geometric mean/ terminal half-life /of/ 13.7 hr.

Nintedanib is a small molecule, competitive, triple angiokinase inhibitor that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Many of these RTKs are implicated in lung fibrosis and tumour angiogenesis, so nintedanib is therefore used in the treatment of proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease. The specific RTKs that nintedanib inhibits are platelet-derived growth factor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fns-Like tyrosine kinase-3 (FLT3). Nintedanib binds to the ATP-binding pocket of these receptors and inhibits their activity, thereby blocking signalling cascades that result in the proliferation and migration of lung fibroblasts. Nintedanib also inhibits kinase signalling pathways in various cells within tumour tissues, including endothelial cells, pericytes, smooth muscle cells, and cells contributing to angiogenesis, culminating in an inhibition of cell proliferation and apoptosis of affected tumour cells. In addition to RTK inhibition, nintedanib also prevents the actions of the nRTKs Lck, Lyn, and Src. The contribution of the inhibition of Lck and Lyn towards the therapeutic efficacy of nintedanib is unclear, but inhibition of the Src pathway by nintedanib has been shown to reduce lung fibrosis.|Idiopathic pulmonary fibrosis (IPF) is a disease with relentless course and limited therapeutic options. Nintedanib (BIBF-1120) is a multiple tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of IPF. The precise antifibrotic mechanism(s) of action of nintedanib, however, is not known. Therefore, we studied the effects of nintedanib on fibroblasts isolated from the lungs of patients with IPF. Protein and gene expression of profibrotic markers were assessed by Western immunoblotting and real-time PCR. Autophagy markers and signaling events were monitored by biochemical assays, Western immunoblotting, microscopy, and immunofluorescence staining. Silencing of autophagy effector proteins was achieved with small interfering RNAs. Nintedanib down-regulated protein and mRNA expression of extracellular matrix (ECM) proteins, fibronectin, and collagen 1a1 while inhibiting transforming growth factor (TGF)-beta1-induced myofibroblast differentiation. Nintedanib also induced beclin-1-dependent, ATG7-independent autophagy. Nintedanib's ECM-suppressive actions were not mediated by canonical autophagy. Nintedanib inhibited early events in TGF-beta signaling, specifically tyrosine phosphorylation of the type II TGF-beta receptor, activation of SMAD3, and p38 mitogen-activated protein kinase. Nintedanib down-regulates ECM production and induces noncanonical autophagy in IPF fibroblasts while inhibiting TGF-beta signaling. These mechanisms appear to be uncoupled and function independently to mediate its putative antifibrotic effects.|Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) a and beta, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology. In addition, nintedanib inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT3 and nRTK inhibition to IPF efficacy is unknown.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Arterial thromboembolic events (e.g., myocardial infarction (MI)) have been reported in patients receiving nintedanib. In clinical studies, arterial thromboembolism was reported in 2.5% of nintedanib-treated patients compared with 0.8% of placebo recipients. MI occurred in 1.5% of patients receiving nintedanib. Nintedanib should be used with caution in patients with cardiovascular risks, including coronary artery disease. The manufacturer states that treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischemia.|/SIGNS AND SYMPTOMS/ Nintedanib may increase the risk of GI perforation based on its mechanism of action. GI perforation was reported in 0.3% of nintedanib-treated patients in clinical studies. Nintedanib should be used with caution in patients who have had recent abdominal surgery. In patients with risk factors for GI perforation, nintedanib should be used only if the potential benefit outweighs the risk. Nintedanib therapy should be discontinued in patients who develop GI perforation.|/CASE REPORTS/ Nintedanib is a multi-target receptor tyrosine kinase inhibitor. In two recent randomized phase 3 trials (INPULSIS-1 and -2), it has been shown to slow the disease progression of idiopathic pulmonary fibrosis (IPF) by reducing the decline in the forced vital capacity (FVC). Although the INPULSIS trials indicate that nintedanib may serve to prevent acute exacerbations or delay the time to the first acute exacerbation, a certain number of IPF patients develop acute exacerbations while receiving nintedanib. However, there has been no report on the readministration of nintedanib in IPF patients who develop acute exacerbations during initial treatment with nintedanib. A 64-year-old man with IPF had nintedanib added to his ongoing pirfenidone therapy. He developed dyspnea after 65 days and presented with hypoxemia after 68 days. At presentation, chest computed tomography showed newly developed diffuse ground glass opacities with the pre-existing subpleural reticular shadows. Because of the absence of infection or other potential causative factors, we diagnosed an acute exacerbation of IPF. Nintedanib was temporarily discontinued and the acute exacerbation was successfully managed with intensive treatment. We re-initiated nintedanib 30 days after cessation, which helped stabilize his FVC for 8 months. Nintedanib was safely continued for 28 months until he died of a bacterial infection. To the best of our our knowledge, this is the first reported case of an acute exacerbation of IPF during nintedanib treatment, wherein nintedanib was safely and successfully restarted after treatment of the acute exacerbation. Our case indicates that nintedanib can be safely resumed and a desired effect on FVC can be obtained, even in IPF patients who develop acute exacerbations. However, we recommend close monitoring and appropriate measures until the long-term safety profile is clarified.|/CASE REPORTS/ In the trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events. Overdose was also reported in two patients in oncology studies who were exposed to a maximum of 600 mg twice daily for up to 8 days. Adverse events reported were consistent with the existing safety profile of Ofev. Both patients recovered.|For more Human Toxicity Excerpts (Complete) data for Nintedanib (6 total), please visit the HSDB record page.

BIBF 1120

Table: Nintedanib Esylate Preparations [Table#8363]

Human drugs -> Vargatef -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Ofev -> EMA Drug Category|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients