Approval Date.
Nedanib Ethanesulfonate Softgels
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Nintedanib Esilate Soft Capsules
English Name: Nintedanib Esilate Soft Capsules
Trade name: Vigat® / Ofev®
Hanyu Pinyin: Yihuangsuan Nidanibu Ruanjiaonang
Ingredients
The main ingredient of this product is: Nidanib Ethanesulfonic Acid
Chemical name: 1H-indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-, methyl ester,(3Z)-, ethanesulfonate (1:1)
Chemical structure formula.
Molecular formula: C31H33N5O4 – C2H6O3S or C33H39N5O7S
Molecular weight: 649.76 g/mol (ethanesulfonate)
539.62 g/mol (free base)
【Properties
This product is a light pink-brown (100mg specification) or brown (150mg specification) opaque oval soft capsule, the contents of bright yellow viscous suspension.
Indications
This product is used for the treatment of idiopathic pulmonary fibrosis (IPF).
Specification
According to the calculation of C31H33N5O4 (1) 100 mg (2) 150 mg.
Dosage and Administration
Treatment with this product should be initiated by a physician with experience in the diagnosis and treatment of IPF.
The recommended dose of this product is 150 mg twice a day at an approximate dosing interval of 12 hours.
The dose may be reduced to 100 mg twice daily as tolerated by the patient. Liver function should be checked before the start of treatment and periodically during the course of administration, and the dose should be reduced or discontinued in case of abnormal liver function (see [Precautions], [Adverse Reactions]).
This product should be taken with food and the whole capsule should be delivered with water. This product has a bitter taste and should not be chewed or crushed. The effect of chewing or crushing the capsule on the pharmacokinetics of nidanib is not known.
If a dose is missed, the recommended dose should be continued at the next scheduled dosing time and the missed dose should not be made up. The recommended maximum daily dose of 300 mg should not be exceeded.
Dose Adjustment
If applicable, in addition to symptomatic treatment, the management of adverse reactions to this product (see [Precautions], [Adverse Reactions]) may include dose reduction and temporary interruption of dosing until the specific adverse reaction resolves to a level that permits continuation of therapy. Treatment may be restarted at the full dose (150 mg twice daily) or at a reduced dose (100 mg twice daily). If the patient cannot tolerate 100 mg twice daily, treatment should be discontinued.
Elevated liver enzymes may require dose adjustment or treatment interruption. If aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increases within 1. 5 times the upper limit of normal (ULN) and there is no evidence of moderate liver injury (Child Pugh B), treatment may be interrupted or the dose may be reduced to 100 mg twice daily. Treatment with the reduced dose (100 mg twice daily) may be resumed when the liver enzymes return to baseline values and may be subsequently increased to the full dose (150 mg twice daily).
The product should be discontinued when AST or ALT>1.5 times ULN, or when there are signs or symptoms of moderate liver injury (Child Pugh B).
Use with caution in patients with mild hepatic injury (Child Pugh Class A).
Special Populations
Pediatric population
The safety and efficacy of this product in pediatric patients have not been studied in clinical trials.
Elderly patients (≥65 years of age)
No overall differences in safety and efficacy have been observed in elderly patients compared to patients younger than 65 years of age. No adjustment of the starting dose based on patient age is required (see [Pharmacokinetics]). Adverse effects are more likely to require management by dose reduction in patients ≥75 years of age.
Ethnicity
No adjustment of the starting dose of this product is required based on population pharmacokinetic (PK) analysis (see [Precautions], [Pharmacokinetics]). Safety data for black patients are limited.
Age, Weight, and Sex
Based on population pharmacokinetic analyses, age and body weight were associated with nidanib exposure. However, they have little effect on exposure and no dose adjustment is required. Gender had no effect on nidanib exposure (see [Pharmacokinetics]).
Renal Injury
Less than 1% of a single dose of nidanib is excreted renally (see [Pharmacokinetics]). No adjustment of the starting dose in patients with mild to moderate renal impairment is required. The safety, efficacy and pharmacokinetics of nidanib have not been studied in patients with severe renal impairment (creatinine clearance < 30 ml/min).
Hepatic Injury
Nedanib is eliminated primarily by biliary/fecal excretion (> 90%); its exposure is increased in patients with hepatic injury (Child Pugh A, Child Pugh B) (see [Pharmacokinetics]).
Use with caution in patients with mild hepatic impairment (Child Pugh A).
In patients with mild hepatic impairment (Child Pugh A), consider interrupting or discontinuing therapy while managing adverse reactions.
The safety and efficacy of nidanib have not been studied in patients with liver injury classified as Child Pugh B and C. Therefore, the use of this product is not recommended for the treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) liver injury (see [Pharmacokinetics]).
Smokers
Smoking is associated with reduced exposure to this product. This may alter the efficacy of this product. Patients are encouraged to stop smoking prior to treatment with this product and to avoid smoking during the use of this product.
[Adverse Reactions].
Safety Summary
Nedanib has been studied in several clinical trials in 1529 patients with idiopathic pulmonary fibrosis (IPF). The safety data presented below are based on two 52-week phase 3, randomized, double-blind, placebo-controlled studies (INPULSIS-1 and INPULSIS-2) involving 1061 patients given nidanib 150 mg twice daily compared to placebo. The most common adverse events associated with the use of nidanib included diarrhea, nausea and vomiting, abdominal pain, loss of appetite, weight loss, and elevated liver enzymes. See [Precautions] for management of corresponding adverse reactions. A summary and frequency classification of adverse reactions is provided by the Medication Administration Standard Medical Terminology Set (MedDRA) Systematic Organ Classification (SOC) (e.g., Table 1).
Table 1 Frequency summary of adverse drug reactions (ADRs) reported in the nidanib group (638 patients) or post-marketing in two 52-week placebo-controlled phase 3 clinical trials
Definitions according to the following frequency categories: very common: ≥1/10; common: ≥1/100 to <1/10; occasional: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; unknown (could not be estimated from the available data).
In each frequency group, adverse reactions are listed in order of decreasing severity.
Table 1.
Summary of ADRs by frequency
Frequency
System Organ Classification Very common (≥ 1/10) Common (≥ 1/100 < 1/10) Occasional (≥ 1/1,000 < 1/100) Blood and lymphatic system disorders Thrombocytopenia Metabolic and nutritional disorders Weight loss, loss of appetite Vascular disorders Hemorrhage1,2 Hypertension Gastrointestinal disorders Diarrhea, nausea, abdominal pain Vomiting Pancreatitis Hepatobiliary disorders Elevated liver enzymes Alanine aminotransferase (ALT) elevated alanine aminotransferase (ALT), elevated
elevated aspartate aminotransferase (AST), elevated
elevated gamma-glutamyl transferase (GGT) hyperbilirubinemia, elevated alkaline phosphatase (ALKP), drug-induced liver injury 1) The term represents a group of events used to describe a broad medical concept rather than an individual disease or a preferred term in a MedDRA (PT).
2) Non-serious and serious bleeding events, some of which are lethal, observed in the post-marketing phase.
Description of specific adverse reactions
Diarrhea
Diarrhea was reported in 62.4% of patients using nidanib. Events of severe intensity accounted for 3.3% of the nidanib treatment group. The first occurrence of diarrhea was in the first three months of treatment in more than two-thirds of patients. Diarrhea led to permanent treatment discontinuation in 4.4% of patients, while the remaining patients were able to manage such events with antidiarrheal therapy, dose reduction, or treatment interruption (see [Precautions]).
Elevated liver enzymes
Liver enzyme elevations were reported in 13.6% of patients on nidanib (see [Precautions]). Elevations in liver enzymes are reversible and do not lead to clinically significant liver disease. See [Precautions] and [Dosage] for more information on special populations, recommended measures and dose adjustments in the event of elevated liver enzymes and diarrhea.
Thrombocytopenia
Thrombocytopenia may occur, and serious cases leading to bleeding have been reported. Monitor the patient carefully, for example by performing regular blood tests. If any abnormalities are observed, appropriate measures should be taken, such as discontinuing treatment with this product.
Occurrence of adverse reactions in major clinical trials
The incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared with the incidence observed in clinical trials of another drug, nor does it reflect the incidence observed in clinical practice, because of the large differences between the conditions under which different clinical trials are conducted.
The safety of this product was evaluated in clinical trials in more than 1,000 patients with IPF, including more than 200 patients who were exposed to this product for more than 2 years.
It was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In one phase 2 (TOMORROW) and two phase 3 (INPULSIS-1 and INPULSIS-2) trials, 723 patients with IPF received 150 mg of this product twice daily, while 508 patients received placebo. The median duration of exposure was 10 months in patients treated with this product compared to 11 months in placebo-treated patients. Subjects ranged in age from 42 to 89 years (median age 67 years). The majority of patients were male (79%) and Caucasian (60%).
The most common serious adverse reactions reported by patients treated with this product (more than in the placebo group) included bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death reported in patients treated with this product (more than in the placebo group) included pneumonia (0.7% versus 0.6%), pulmonary malignancy (0. 3% versus 0%) and myocardial infarction (0.3% versus 0.2%). In the pre-defined category of major adverse cardiovascular events (MACE) including myocardial infarction, fatal events were reported in 0.6% of patients treated with this product and 1.8% of patients treated with placebo.
Adverse reactions resulting in permanent dose reductions were reported in 16% of patients treated with this product and 1% of patients treated with placebo. The most common adverse reaction resulting in permanent dose reduction reported by patients treated with this product was diarrhea (11%).
Adverse reactions leading to discontinuation of therapy were reported by 21% of patients treated with this product and 15% of patients treated with placebo. The most common adverse reactions reported by patients treated with this product that led to discontinuation of treatment were diarrhea (5%), nausea (2%), and loss of appetite (2%).
In addition, patients treated with this product reported more hypothyroidism (1.1% vs. 0.6%) compared to patients treated with placebo.
[Contraindications].
This product is contraindicated in patients with known hypersensitivity to nidanib, peanut, soy, or any of the excipients of this product.
This product is contraindicated in patients with moderate (Child Pugh B) or severe (Child Pugh C) liver injury.
This product is contraindicated during pregnancy (see [Pregnancy and Lactation] and [Pharmacology and Toxicology]).
Precautions
Gastrointestinal disorders
Diarrhea
In the two INPULSIS trials (see [Clinical Trials]), diarrhea was the most common gastrointestinal event, reported in 62.4% of patients treated with this product and 18.4% of patients treated with placebo, respectively (see [Adverse Reactions]). In the majority of patients, the event was mild to moderate in severity and occurred within the first 3 months of treatment. Diarrhea resulted in a decrease in drug dose in 10.7% of patients and led to discontinuation of therapy in 4.4% of patients.
Treatment with appropriate rehydration and antidiarrheal medications, such as loperamide, should be administered at the time of first presentation of diarrhea and may require treatment interruption. Treatment with this product may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). If severe diarrhea persists even after symptomatic treatment, treatment with this product should be discontinued.
Nausea and vomiting
Nausea and vomiting are frequently reported adverse events (see [ADVERSE REACTIONS]). In the majority of patients with nausea and vomiting, the event was mild to moderate in severity. Nausea resulted in discontinuation of nidanib therapy in 2.0% of patients. Vomiting resulted in discontinuation of nidanib therapy in 0.8% of patients.
If symptoms persist despite appropriate supportive therapy (including antiemetic therapy), then a dose reduction or interruption of therapy may be warranted. Treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). If severe symptoms persist even after symptomatic treatment, treatment with this product should be discontinued.
Diarrhea and vomiting may lead to dehydration and/or electrolyte disturbances.
Liver Function
The safety and efficacy of this product has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) liver injury. Therefore, this product is contraindicated in patients with moderate or severe liver injury.
In patients with mild hepatic injury (Child Pugh A), the risk of adverse events may increase with increasing exposure. Use this product with caution in patients with mild liver injury. Patients with mild hepatic injury (Child Pugh A) should receive reduced dose therapy (see [Dosage], [Pharmacokinetics]).
Cases of drug-induced liver injury have been clinically observed in nedanib therapy. Nedanib administration may be associated with elevated liver enzymes (ALT, AST, alkaline phosphatase (ALKP), gamma-glutamyl transferase (GGT)) and bilirubin. The elevation of aminotransferases and bilirubin is reversible with dose reduction or treatment interruption. Liver function tests (ALT, AST, and bilirubin) should be performed before treatment with this product, monthly for 3 months thereafter, and every 3 months thereafter, respectively; or as clinically indicated. Elevated liver enzymes may require dose adjustment or interruption of therapy (see [DOSAGE AND ADMINISTRATION]).
Patients weighing less than 65 kg, Asian and female patients have a higher risk of elevated liver enzymes. Nedanib exposure increases linearly with patient age, which may also lead to an increased risk of elevated liver enzymes (see [Pharmacokinetics]). Close monitoring of patients with these risk factors is recommended.
If an increase in aminotransferase (AST or ALT) within 1.5 times the upper limit of normal (ULN) is detected without signs of moderate liver injury (Child Pugh B), dose reduction or interruption of therapy is recommended and the patient should be monitored closely. Once aminotransferases return to baseline values, treatment may be increased again to the full dose (150 mg twice daily) or restarted at a reduced dose (100 mg twice daily) with subsequent increases to the full dose (see [DOSAGE AND ADMINISTRATION]). If any elevated liver function tests are accompanied by clinical signs or symptoms of liver injury, such as jaundice, treatment with this product should be permanently discontinued. Other possible causes of elevated liver enzymes should be sought.
Bleeding
Inhibition of the vascular endothelial growth factor receptor (VEGFR) may be associated with an increased risk of bleeding. In the two INPULSIS trials with this product, patients in the nidanib-treated group (10.3%) had a slightly higher frequency of bleeding adverse events than in the placebo group (7.8%). The most common bleeding event was non-serious epistaxis. The frequency of serious bleeding events was lower and similar in both treatment groups (placebo group: 1.4%; nedanib-treated group: 1.3%).
The two INPULSIS studies did not enroll patients with a known risk of bleeding, which included congenital bleeding tendency or treatment with a full dose of anticoagulant. Post-marketing, cases of bleeding have been reported, including patients who received or did not receive anticoagulant therapy or other medications that can cause bleeding. Therefore, this product was given to these patients only if the expected benefit outweighed the potential risk.
Non-serious and serious bleeding events, some of which were fatal, have been observed during the post-marketing period.
Embryo-fetal toxicity
Based on the results of animal studies and its mechanism of action, this product can be harmful to the fetus when administered to pregnant females. Nidanib caused embryo-fetal death and structural abnormalities in rats and rabbits when given at less than (rats) and near (rabbits) 5 times the maximum recommended adult human dose (MRHD) during the organogenesis phase. Pregnant females should be informed of the potential risk of this product to the fetus. Women of childbearing potential should be advised to avoid pregnancy during treatment with this product and to use effective contraception during treatment with this product and for at least 3 months after the last dose. Check pregnancy status before receiving this product for administration.
Arterial Thromboembolism
Two INPULSIS trials excluded patients with a history of recent myocardial infarction or stroke. Reported arterial thromboembolic events were rare: 0.7% of patients in the placebo group and 2.5% of patients in the nidanib-treated group reported the event. Although adverse events reflecting ischemic heart disease were balanced between the nidanib-treated and placebo groups, the percentage of patients who experienced myocardial infarction was higher in the nidanib-treated group (1.6%) compared with the placebo group (0.5%). Caution should be exercised in patients with higher cardiovascular risk, including those with known concomitant coronary artery disease. Treatment interruption should be considered in patients presenting with signs or symptoms of acute myocardial ischemia.
Venous thromboembolism
In the two INPULSIS trials, an increased risk of venous thromboembolism was not observed in patients treated with nidanib. Considering the mechanism of action of nidanib, patients may be at increased risk of thromboembolic events.
Gastrointestinal perforation
An increased risk of gastrointestinal perforation was not observed in patients treated with nidanib in the two INPULSIS trials. Considering the mechanism of action of nidanib, patients may be at increased risk of gastrointestinal perforation. Cases of gastrointestinal perforation have been reported during the post-marketing period. Particular caution should be exercised when treating patients who have undergone prior abdominal surgery, patients with a recent history of cavity organ perforation, patients with a history of peptic ulcer, diverticular disease, or patients on a combination of corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs). Treatment with this product should be initiated at least 4 weeks after major surgery (including abdominal surgery). Treatment with this product should be permanently discontinued in patients who develop gastrointestinal perforation.
Hypertension
This product may cause an increase in blood pressure. Systemic blood pressure should be tested regularly and at the time of clinical presentation.
Wound healing complications
An increased frequency of wound healing effects was not observed in the two INPULSIS trials. Considering the mechanism of action, nidanib may affect wound healing. Specific studies on the effect of nidanib on wound healing have not been performed. Therefore, treatment with this product can only be initiated based on clinical judgment of adequate wound healing or resumed after interruption of dosing during the perioperative period.
QT interval effects
No evidence of QT interval prolongation with nidanib was found in the clinical trial program (see [Clinical Trials]). Because certain other tyrosine kinase inhibitors have a prolonging effect on the QT interval, greater caution should be exercised when giving nidanib treatment to patients who may experience QTc prolongation.
Soy Lecithin
This softgel contains soy lecithin, which can trigger allergic reactions, including severe fast-onset allergic reactions, in patients with soy allergy to soy products. Patients who are allergic to peanut proteins are also at increased risk of severe reactions to soy products (see [Contraindications]).
Effects on driving and machine handling ability
No studies have been conducted on the effects of this product on driving and the ability to operate machinery. Patients are advised to drive or operate machinery with caution during treatment with this product.
Pregnant and lactating women
Women of childbearing potential and contraception
Nedanib may cause fetal damage in humans. It is recommended that women of childbearing potential should avoid pregnancy while receiving this product. Women of childbearing potential receiving nidanib are advised to use effective contraception during treatment with nidanib and for at least 3 months after the last dose. As the effect of nidanib on the metabolism and efficacy of hormonal contraceptives has not been studied, the barrier method should be used as a second form of contraception to avoid pregnancy.
Pregnancy
There is no information on the use of this product in pregnant women, but preclinical studies performed in animals have shown reproductive toxicity of the drug (see [Pharmacologic Toxicology]). Because nidanib may also cause fetal harm in humans, it should not be used during pregnancy, or at least a pregnancy test should be performed prior to treatment with this product.
Female patients are advised to notify their physician or pharmacist if they become pregnant while receiving this product.
If a patient becomes pregnant while receiving this product, the patient should be informed of the potential for fetal harm. Discontinuation of therapy should be considered.
Lactation
No information is available on the excretion of nidanib and its metabolites in human breast milk. Preclinical studies have shown that small amounts of nidanib and its metabolites (≤ 0.5% of the administered dose) are secreted into the milk of lactating rats. The risk to neonates/infants cannot be excluded. Lactation should be discontinued during treatment with this product.
Fertility
Based on preclinical studies, there is no evidence of impaired fertility in males. Based on the results of subchronic and chronic toxicity studies, there is no evidence of impaired fertility in female rats at systemic exposure levels comparable to the maximum recommended human dose (MRHD) of 150 mg twice daily (see [Pharmacology and Toxicology]).
Pediatric Dosage]
Clinical trials have not been conducted in children and adolescents.
Geriatric Use
No overall differences in safety and efficacy have been observed in elderly patients compared to patients younger than 65 years of age. There is no need to adjust the starting dose according to the patient’s age. Adverse effects are more likely to be managed by dose reduction in patients ≥75 years of age (see [Pharmacokinetics]).
Drug Interactions
P-glycoprotein (P-gp)
Nedanib is a substrate for P-gp (see [Pharmacokinetics]). In a drug interaction-specific study, coadministration of the potent inhibitor of P-gp, ketoconazole, increased exposure to nidanib up to 1.61-fold when measured by area under the drug-time curve (AUC) and up to 1.83-fold when measured by peak concentration (Cmax).
In a drug interaction study with the coadministration of the P-gp potent inducer rifampicin, the coadministration of rifampicin decreased exposure to nidanib to 50.3% by area under the curve (AUC) and 60.3% by peak concentration (Cmax) compared to nidanib alone.
P-gp potent inhibitors (e.g., ketoconazole or erythromycin) may increase nidanib exposure if co-administered with this product. In these cases, patient tolerance to nidanib should be closely monitored. Management of adverse reactions may require interruption, dose reduction, or discontinuation of this product (see [DOSAGE]).
P-gp potent inducers (e.g., rifampin, carbamazepine, phenytoin, and St. John’s wort) may reduce nidanib exposure. Alternative combinations of drugs without P-gp induction or with minimal induction should be considered.
Food
Concomitant administration of this product with food is recommended (see [Pharmacokinetics]).
Cytochrome (CYP)-enzyme
Bioconversion of nidanib is only marginally dependent on the CYP pathway. In preclinical studies, nidanib and its metabolites (the free acid fraction BIBF 1202 and its glucosinolate compound BIBF 1202 glucosinolate) did not inhibit or induce CYP enzymes (see [Pharmacokinetics]). Therefore, the likelihood of drug interactions occurring with nidanib based on CYP metabolism is considered to be low.
Co-administration with other drugs
Potential interactions of nidanib with hormonal contraceptives have not been explored.
Nedanib has pH-dependent solubility properties, with increased solubility in an acidic environment at pH<3. However, co-administration with proton pump inhibitors or histamine H2 antagonists had no effect on nidanib exposure (trough concentrations) in clinical trials.
Anticoagulants
Nedanib is a VEGFR inhibitor and may increase the risk of bleeding. Patients receiving full-dose anticoagulation should be closely monitored for bleeding and anticoagulation should be adjusted if necessary.
[Overdose].
There is no specific antidote or treatment for overdose of this product. The maximum single dose of nidanib given in the phase 1 study was 450 mg once daily. In addition, 2 patients in the oncology program experienced a maximum overdose of 600 mg given twice daily for 8 days. The observed adverse reactions were consistent with the known safety profile of nidanib, namely elevated liver enzymes and gastrointestinal symptoms. Both patients recovered from these adverse reactions.
In the INPULSIS trial, one patient was accidentally exposed to a dose of 600 mg once daily for 21 days. A non-serious adverse event (nasopharyngitis) occurred during the incorrect dosing and subsequently recovered, with no other events reported.
In the case of drug overdose, treatment should be interrupted and routine supportive measures initiated as needed.
[Clinical Trials].
The clinical effectiveness of nidanib in patients with IPF was investigated in two identically designed phase 3, randomized, double-blind, placebo-controlled studies (INPULSIS-1 and INPULSIS-2). Patients with baseline FVC<50% of normal predicted or lung carbon monoxide diffusion function (DLCO, corrected for hemoglobin)<30% of normal baseline predicted were excluded from the clinical trials. Patients were randomized in a 3:2 ratio to either 150 mg of this product or placebo twice daily for 52 weeks.
The primary endpoint was the annual rate of decline in exertional spirometry (FVC). Key secondary endpoints were the value of the change in total St. George’s Respiratory Questionnaire (SGRQ) score relative to baseline at 52 weeks and the time to the first acute exacerbation of IPF.
The annual rate of decline in FVC
The annual rate of decline in FVC (in mL) was significantly lower in patients treated with nidanib compared with those treated with placebo. The treatment effects were consistent between the two studies. Individual and pooled study results are shown in Table 2.
Table 2 Annual rate of decline in FVC (in mL) in trials INPULSIS-1, INPULSIS-2 and their pooled data – treatment set
INPULSIS-1 INPULSIS-2 Pooled INPULSIS-1 vs. INPULSIS-2 Placebo nidanib 150 mg
Placebo nidanib 150 mg twice daily
Twice-daily placebo nidanib 150 mg
Number of patient cases analyzed twice daily 204 309 219 329 423 638 Rate of decline over 52 weeks1 (SE) -239.9
(18.71)-114.7
(15.33)-207.3
(19.31) -113.6
(15.73)-223.5
(13.45) -113.6
(10.98) Difference compared to placebo1
125.3
93.7
109.9 95% CI (77.7,172.8) (44.8,142.7) (75.9,144.0) P-value < 0.0001 0.0002 < 0.0001 1 Estimates based on random coefficient regression models.
The robustness of the effect of nidanib on the annual rate of decline in FVC was confirmed in all prespecified sensitivity analyses.
In addition, similar results were observed for other pulmonary function endpoints such as change in FVC relative to baseline at week 52 and in the analysis of FVC responders that further confirmed the effect of nidanib on delaying disease progression. The evolution over time of the changes relative to baseline in both treatment groups, based on a pooled analysis of studies INPULSIS-1 and INPULSIS-2, is shown in Figure 1.
Figure 1 Evolution over time of the mean (SEM) of the observed changes in FVC relative to baseline (mL) for the pooled studies INPULSIS-1 and INPULSIS-2
bid = twice daily
Analysis of FVC Responders
In both INPULSIS trials, the rate of FVC responders was significantly higher in the nidanib group compared with the placebo group.FVC responders were defined as an absolute decrease of no more than 5% of the % predicted value of FVC (a critical predictor of elevated risk of death in IPF). Similar results were observed in analyses performed using a conservative cut-off value of 10%. The results of the individual and pooled studies are shown in Table 3.
Table 3 Proportion of FVC responders at 52 weeks in INPULSIS-1, INPULSIS-2 and their pooled data – treatment set
INPULSIS-1 INPULSIS-2 Pooled INPULSIS-1 vs. INPULSIS-2 Placebo nidanib 150 mg
Placebo nidanib 150 mg twice daily
Twice-daily placebo nidanib 150 mg
Number of patients analyzed twice daily 204 309 219 329 423 638 5% critical value Number of FVC responders (%) 178 (38.2) 163 (52.8) 86 (39.3) 175 (53.2) 164 (38.8) 338 (53.0) compared to placebo Ratio 1.85 1.79 1.84 95% CI (1.28 , 2.66) (1.26, 2.55) (1.43, 2.36) P value2 0.0010 0.0011 < 0.0001 10% critical value Number of FVC responders (%) 1116 (56.9) 218 (70.6) 140 (63.9) 229 (69.6) 256 (60.5) 447 (70.1) vs placebo Comparison Ratio 1.91 1.29 1.58 95% CI (1.32, 2.79) (0.89, 1.86) (1.21, 2.05) P-value2 0.0007 0.1833 0.0007 1 Responders were patients with an absolute decrease of no more than 5% or 10% of the predicted value of FVC%, according to the critical value and evaluation at week 52.
2Based on logistic regression
Time to progression (≥10% absolute decline in FVC% predicted or death)
In the two separate INPULSIS trials, patients treated with nidanib had a statistically significant reduction in the risk of progression compared with placebo. In the pooled analysis, the risk ratio (HR) was 0.60, indicating a 40% reduction in the risk of progression in patients treated with nidanib compared with placebo, as shown in Table 4.
Table 4 Proportion of patients with an absolute decrease in FVC% predicted by ≥10% or death at 52 weeks and trials INPULSIS-1, INPULSIS-2 and their pooled data to time to progression – treatment set
INPULSIS-1 INPULSIS-2 INPULSIS-1 and INPULSIS-2 Summary Placebo Nedanib
150mg
Placebo nidanib twice daily
150mg
Placebo Nedanib twice daily
150mg
Number of twice-daily risk patients 204 309 219 329 423 638 Patients with concomitant events, N (%) 83
(40.7) 75
(24.3) 92
(42.0) 98
(29.8) 175
(41.4) 173
(27.1) Compared with placebo1 p-value2 0.0001 0.0054 <0.0001 Risk ratio3 0.53 0.67 0.60 95% CI (0.39, 0.72) (0.51, 0.89) (0.49, 0.74)1 Based on data collected up to 372 days (52 weeks + 7 days).
2Based on Log-rank test.
3Based on Cox’s regression model.
Change in SGRQ total score at week 52 relative to baseline
The St. George’s Respiratory Questionnaire (SGRQ) total score measuring health-related quality of life (HRQoL) was analyzed at week 52. In INPULSIS-2, the increase in total SGRQ scores relative to baseline was greater in patients treated with placebo compared to those treated with nedanib 150 mg twice daily. The worsening of HRQoL was smaller in the nidanib group; the difference between the two treatment groups was statistically significant (-2.69; 95% CI: -4.95, -0.43; p = 0.0197).
In INPULSIS-1, the increase in total SGRQ score at week 52 relative to baseline was comparable between the nidanib and placebo groups (difference between treatment groups: -0.05; 95% CI: -2.50, 2.40; p = 0.9657). In a pooled analysis of the two INPULSIS trials, the estimated mean change in total SGRQ score from baseline to week 52 was smaller in the nidanib group (3.53) compared with the placebo group (4.96), with a difference between treatment groups of -1.43 (95% CI: -3.09, 0.23; p = 0.0923). Overall, nidanib had some effect on health-related quality of life measured using the SGRQ total score, indicating slower deterioration compared with the placebo group.
Time to first acute exacerbation of IPF
In the INPULSIS-2 trial, patients treated with nidanib had a significantly lower risk of first acute exacerbation of IPF over a 52-week period compared with the placebo group, and in the INPULSIS-1 trial there was no difference between the two treatment groups. In a pooled analysis of the two INPULSIS trials, a numerically lower risk of first acute exacerbation was observed in patients treated with nidanib compared to the placebo group. The results of the individual and pooled studies are shown in Table 5.
Table 5 Time to first acute exacerbation at 52 weeks based on investigator-reported events in trials INPULSIS-1, INPULSIS-2 and their pooled data – treatment set
INPULSIS-1 INPULSIS-2 pooled INPULSIS-1 vs. INPULSIS-2 Placebo nidanib 150 mg
Twice-daily placebo nidanib 150 mg
Twice-daily placebo nidanib 150 mg
Number of patients at risk twice daily 204 309 219 329 423 638 Patients with concomitant events, N (%) 11 (5.4) 19 (6.1) 21 (9.6) 12 (3.6) 32 (7.6) 31 (4.9) Compared with placebo1 P value2 0.6728 0.0050 0.0823 Risk ratio3 1.15 0.38 0.6495% CI (0.54, 2.42) (0.19,0.77) (0.39,1.05)1 Based on data collected up to 372 days (52 weeks + 7 days).
2Based on Log-rank test.
3Based on Cox regression model.
All investigator-reported acute exacerbation adverse events in IPF were adjudicated by a blinded adjudication committee. Predetermined sensitivity analyses were performed using pooled data for time to first adjudication as a “confirmed” or “suspected” acute exacerbation of IPF. The frequency of patients with at least one adjudicated exacerbation within 52 weeks was less in the nidanib group (1.9% of patients) than in the placebo group (5.7% of patients). The hazard ratio (HR) obtained for the time-to-event analysis using pooled data for adjudicated exacerbations was 0.32 (95% CI: 0.16, 0.65; p = 0.0010). This indicates a statistically significant reduction in the risk of a first acute exacerbation of IPF in the nidanib group compared with the placebo group at all time points.
Survival analysis
In a pre-specified pooled analysis of survival data from the INPULSIS trial, the nidanib group had a lower overall mortality rate at 52 weeks (5.5%) compared with the placebo group (7.8%). Time to death analysis resulted in a risk ratio (HR) of 0.70 (95% CI: 0.43, 1.12; p = 0.1399). Results for all survival endpoints (e.g., on-treatment mortality and respiratory mortality) showed consistent numerical differences in favor of nidanib, as shown in Table 6.
Table 6 All-cause mortality within 52 weeks for trials INPULSIS-1, INPULSIS-2 and their pooled data – treatment set
INPULSIS-1 INPULSIS-2 INPULSIS-1 and INPULSIS-2 Summary Placebo Nedanib
150 mg
Placebo nidanib twice daily
150mg
Placebo Nedanib twice daily
150mg
Number of patients exposed twice daily 204 309 219 329 423 638 Patients with concomitant events, N (%) 13 (6.4) 13 (4.2) 20 (9.1) 22 (6.7) 33 (7.8) 35 (5.5) Compared with placebo1 p-value2 0.2880 0.2995 0.1399 Risk ratio3 0.63 0.74 0.70 95% CI (0.29, 1.36) (0.40, 1.35) (0.43, 1.12) 1Based on data collected up to 372 days (52 weeks + 7 days).
2Based on Log-rank test.
3Based on Cox regression model
Supporting evidence from the results of the phase 2 trial (TOMORROW) of this product 150 mg twice daily.
A randomized, double-blind, placebo-controlled, dose-exploratory phase 2 trial that included a twice-daily dose group of nedanib 150 mg provided additional evidence of effectiveness. The rate of decline in FVC over 52 weeks was lower in the nidanib group (-0.060 L/year, N = 84) than in the placebo group (-0.190 L/year, N = 83) for the primary endpoint. The estimated difference between the two treatment groups was 0.131 L/year (95% CI : 0.027, 0.235). The difference between the two treatment groups reached nominal statistical significance (p = 0.0136).
The estimated mean change in total SGRQ score relative to baseline at 52 weeks was 5.46 in the placebo group, indicating deterioration in health-related quality of life, and -0.66 in the nidanib group, indicating stable health-related quality of life. The estimated mean difference in the nidanib group compared with the placebo group was -6.12 (95% CI: -10.57, -1.67; p = 0.0071).
Fewer patients in the nidanib group had an acute exacerbation of IPF at 52 weeks (2.3%, N = 86) compared with the placebo group (13.8%, N = 87). The estimated risk ratio for nidanib compared with placebo was 0.16 (95% CI: 0.04, 0.71; p = 0.0054).
Effect on QT interval
QT/QTc measurements were recorded and analyzed in a specific study of nidanib monotherapy versus sunitinib monotherapy implemented in patients with renal cell carcinoma. In this study, a single oral dose of nidanib 200 mg and multiple oral doses of nidanib 200 mg twice daily for 15 days did not prolong the QTc interval.
[Pharmacology and Toxicology].
Pharmacological effects
Nedanib is a small molecule tyrosine kinase inhibitor with antifibrotic and anti-inflammatory activities. Nedanib inhibits multiple receptor tyrosine kinases (RTK): platelet-derived growth factor receptor α and β (PDGFRα, β), fibroblast growth factor receptor 1-3 (FGFR1-3), vascular endothelial growth factor receptor 1-3 (VEGFR1-3) and Fms-like tyrosine kinase-3 (FLT3), with FGFR, PDGFR and VEGFR are implicated in the pathogenesis of IPF, and nidanib competitively binds to the adenosine triphosphate (ATP) binding sites on the structural domains of these intracellular receptor kinases, blocking intracellular signaling and inhibiting fibroblast proliferation, migration, and transformation. In addition, nidanib inhibits the following non-receptor tyrosine kinases (nRTK): Lck, Lyn and Src kinases. The role of its inhibition of FLT3 and nRTK on the efficacy of IPF is not known.
Toxicological studies
Genotoxicity
The results of the Ames test for nidanib, the in vitro mouse lymphoma cell test, and the in vivo rat micronucleus test were all negative.
Reproductive toxicity
Oral administration of nidanib 100 mg/kg/day to rats (in vivo exposure to rats is close to 3 times the AUC at the maximum recommended adult dose of MRHD) caused impairment of female reproductive function, as evidenced by increased number of absorbed fetuses and embryos lost after implantation and decreased pregnancy index; no adverse effects on the male reproductive system or fertility were observed. Repeated oral administration of nidanib to rats and mice showed changes in the number and size of corpora lutea in female ovaries, and an increase in the number of females with embryo resorption was seen only at a dose of 20 mg/kg/day (exposure equivalent to one times the AUC at the MRHD dose).
In an embryo-fetal developmental toxicity assay, oral administration of nidanib at 2.5 mg/kg/day to pregnant rats and 15 mg/kg/day to pregnant rabbits (
In a 2-year carcinogenicity test, oral administration of nidanib at 10 mg/kg/day and 30 mg/kg/day in mice and rats (exposure of < AUC at MRHD dose and 4 times the AUC at MRHD dose, respectively) did not show carcinogenicity.
Pharmacokinetics]
The pharmacokinetic (PK) profile of nidanib was similar in healthy volunteers, IPF patients and cancer patients. The PK of nedanib was linear. Nedanib exposure increased with increasing dose (dose range 50-450 mg once daily; 150 -300 mg twice daily), demonstrating a dose-proportional relationship. The area under the drug-time curve (AUC) accumulation in IPF patients was 1.76-fold after multiple doses. Steady-state blood concentrations were achieved within 1 week of dosing. Nedanib trough concentrations remained stable for more than 1 year. Inter-individual variability of nidanib PK was moderate to high (coefficient of variation in the range of 30%-70% for standard PK parameters), while intra-individual variability was low to moderate (coefficient of variation less than 40%).
Absorption
Nedanib reaches maximum plasma concentrations approximately 2 – 4 hours (range 0.5 – 8 hours) after oral administration as a softgel in the fed state. The absolute bioavailability of the 100 mg dose in healthy volunteers was 4.69% (90% CI: 3.615 – 6.078). Transporter effects and significant first-pass metabolism decreased absorption and bioavailability.
Dosing was proportional to increasing nidanib exposure (dose range 50 – 450 mg once daily and dose range 150 – 300 mg twice daily). Steady-state plasma concentrations are achieved at least 1 week after dosing.
Nidanib exposure increased by approximately 20% (CI: 95.3 – 152.5%) and absorption was delayed when nidanib was administered after a meal compared to fasting status (median tmax 2.00 hours fasting; postprandial: 3.98 hours).
Distribution
Nedanib complies with minimal biphasic disposition kinetics. After intravenous infusion, a large volume of distribution was observed in the terminal phase (Vss: 1050 L, 45.0% gCV).
In human plasma, the in vitro protein binding of nidanib was high, with a binding fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nedanib is preferentially distributed in plasma, with a blood to plasma distribution ratio of 0.869.
Metabolism
The major metabolic reaction of nidanib is the hydrolytic splitting by esterases, which produces the free base group BIBF 1202. BIBF 1202 is subsequently glucuronidated to BIBF 1202 glucosinolate by UGT enzymes (i.e. UGT 1A1, UGT 1A7, UGT 1A8 and UGT 1A10).
Nedanib is biotransformed only to a small extent via the CYP pathway, with CYP 3A4 being the main enzyme involved. The major CYP-dependent metabolites could not be measured in plasma in human ADME (absorption, distribution, metabolism, elimination) studies. In in vitro studies, CYP-dependent metabolism accounted for approximately 5%, compared to approximately 25% for ester cleavage. Since nidanib, BIBF 1202 and BIBF 1202 glucosinolates did not inhibit or induce CYP enzymes in preclinical studies. Therefore, there are no drug interactions between nidanib and CYP substrates, CYP inhibitors, or CYP inducers.
Elimination
Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min, 28.8% gCV). Urinary excretion of the drug in its original form was approximately 0.05% of the dose (31.5% gCV) within 48 hours of oral administration and approximately 1.4% of the dose (24.2% gCV) after intravenous administration; renal clearance was 20 mL/min (32.6% gCV). The primary route of elimination of drug-related radioactivity after oral administration of [14C]nidanib was via fecal/biliary excretion (93.4% of dose, 2.61% gCV). Renal excretion contributed less to the total clearance (0.649% of dose, 26.3% gCV). Total recovery within 4 days of dosing was considered complete (more than 90%). The terminal half-life of nidanib was 10 to 15 hours (gCV% was approximately 50%).
Transmigration
Nedanib is one of the substrates of P-gp. See [Drug Interactions] for potential interactions between nedanib and this transporter. Nedanib is not shown to be a substrate or inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2 in vitro. Nedanib is also not a substrate of BCRP. Only weak inhibition of OCT-1, BCRP and P-gp was observed in vitro, and its clinical relevance is low. Similar results apply to studies when nedanib is used as a substrate for OCT-1.
Exposure-response relationship
Exposure-response analysis demonstrated an Emax-like relationship between the range of exposures observed in phase 2 and 3 studies and the annual rate of decline in FVC, with an EC50 of approximately 3-5 ng/mL (relative standard error: 54-67%).
In terms of safety, the relationship between nidanib plasma exposure and elevated ALT and/or AST appears to be weak. Even if plasma exposure cannot be excluded as a risk determinant, the actual dose administered may be a better predictor of the risk of diarrhea of any intensity (see [Precautions]).
Population Pharmacokinetic Analysis in Special Populations
The pharmacokinetic properties of nidanib were similar in healthy volunteers, patients with IPF, and patients with cancer. Based on the results of population pharmacokinetic (Pop PK) analyses and descriptive studies performed in patients with IPF and non-small cell lung cancer (NSCLC) (N = 1191), gender (corrected for body weight), mild to moderate renal impairment (as predicted by creatinine clearance), liver metastases, ECOG fitness status score, alcohol consumption, or P-gp genotype did not affect nidanib exposure. Population pharmacokinetic analysis showed moderate effects on nidanib exposure depending on age, weight and ethnicity (see description below). These effects are not considered clinically significant based on the higher interindividual variation in exposure observed in clinical trials (see [Caution]).
Age
Exposure to nidanib increased linearly with age. Relative to the median age of 62 years, the AUCτ,ss decreased by 16% in patients aged 45 years (5th percentile) and increased by 13% in patients aged 76 years (95th percentile). The analysis covered an age range of 29 to 85 years; approximately 5% of the population was older than 75 years. Based on the PopPK model, the increase in nidanib exposure was approximately 20 – 25% in patients aged ≥75 years compared to patients under 65 years. Studies have not been conducted in pediatric populations.
Body weight
Body weight was negatively associated with exposure to nidanib. Relative to patients with a median weight of 71.5 kg, AUCτ,ss increased by 25% in patients weighing 50 kg (5th percentile) and decreased by 19% in patients weighing 100 kg (95th percentile).
Ethnicity
Compared with Caucasians, mean exposure (corrected for body weight) in the nidanib population was elevated by 33-50% in Chinese, Taiwanese, and Indian patients, elevated by 16% in Japanese, and decreased by 16-22% in Koreans.
Data from black individuals are extremely limited, but are in the same range as Caucasians.
Renal injury
Based on a population pharmacokinetic analysis of data from 933 patients with IPF, mild (creatinine clearance: 60-90 mL/min; n=399) or moderate (creatinine clearance: 30-60 mL/min; n=116) renal impairment did not affect nidanib exposure. Data on severe renal impairment (creatinine clearance less than 30 mL/min) are limited.
Hepatic Impairment
In a phase 1 single-dose clinical pharmacokinetic study of this product, eight subjects with mild hepatic impairment (Child Pugh class A) and eight subjects with moderate hepatic impairment (Child Pugh class B) were compared with 17 subjects with normal hepatic function. The mean exposure to nidanib in subjects with mild hepatic impairment was 2.4-fold (90% CI: 1.6-3.6) higher than in subjects with normal liver function according to peak concentration (Cmax); and 2.2-fold (90% CI: 1.4-3.5) higher than in subjects with normal liver function according to AUC0-inf. For subjects with moderate hepatic impairment, mean nidanib exposure was 6.9-fold (90% CI: 4.4-11.0) higher than in subjects with normal liver function by peak concentration (Cmax); and 7.6-fold (90% CI: 5.1- 11.3) higher than in subjects with normal liver function by AUC0-inf. No studies were conducted in subjects with severe hepatic impairment (Child Pugh class C).
Combination therapy with pirfenidone
Nidanib was studied in combination with pirfenidone in a parallel group design study implemented in Japanese patients with IPF. 24 patients received nidanib 150 mg twice daily for 28 days. In 13 patients, nidanib was added to the standard dose of pirfenidone long-term treatment. 11 patients received nidanib monotherapy. Nidanib exposure decreased to 68.3% by AUC and 59.2% by Cmax when nidanib was given on top of pirfenidone compared to nidanib alone. Nedanib had no effect on the PK of pirfenidone. Due to the short duration of the combined exposure and the small number of patients, no conclusions can be drawn regarding the benefit-risk of the combination with pirfenidone.
[Storage].
Please store below 25℃.
Store in a safe place out of the reach and sight of children!
Packaging
Aluminum/aluminum blister package.
30 capsules/box, 60 capsules/box.
Expiration date
36 months.
Execution Standard
Imported drug registration standard JX20160186
【Approval number】
Imported drug registration certificate number: HXXXXXXXXXX
【Manufacturing Company
Company name: Boehringer Ingelheim International GmbH
Address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany (Germany)
Production plant: Catalent Germany Eberbach GmbH
Production address: Gammelsbacher Strasse 2, 69412 Eberbach, Germany (Germany)
Packaging plant: Boehringer Ingelheim Pharma GmbH & Co.
Address: Binger Strasse 173, 55216 Ingelheim am Rhein, Germany (Germany)
Domestic contact unit.
Company name: Boehringer Ingelheim Pharmaceuticals Shanghai Co.
Address: No. 1010 Longdong Avenue, China (Shanghai) Pilot Free Trade Zone
Postal Code: 201203
Phone Number/Product Service Hotline: 400-820-5907, 800-820-5907
Fax Number: (021) 5080 1530
Web address: www.boehringer-ingelheim.com.cn