Nintedanib
- Nintedanib is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

# Dosage

## Testing Prior to Nintedanib Administration
- Conduct liver function tests prior to initiating treatment with nintedanib.

## Recommended Dosage
- The recommended dosage of nintedanib is 150 mg twice daily administered approximately 12 hours apart.
- Nintedanib capsules should be taken with food and swallowed whole with liquid. Nintedanib capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.
- If a dose of nintedanib is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg.

## Dosage Modification due to Adverse Reactions
- In addition to symptomatic treatment, if applicable, the management of adverse reactions of nintedanib may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with nintedanib.
- Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to 5 times ULN or >3 times ULN with signs or symptoms of severe liver damage.
- The safety and efficacy of nintedanib has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Treatment with nintedanib is not recommended in patients with moderate or severe hepatic impairment.
- In clinical trials, administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT). Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. The majority (94%) of patients with ALT and/or AST elevations had elevations <5 times ULN. Administration of nintedanib was also associated with elevations of bilirubin. The majority (95%) of patients with bilirubin elevations had elevations <2 times ULN.
- Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with nintedanib, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations.

# Gastrointestinal Disorders

## Diarrhea
- Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with nintedanib and placebo, respectively. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with nintedanib compared to 0 placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 5% of the patients compared to <1% of placebo-treated patients.
- Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with nintedanib.

## Nausea and Vomiting
- Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with nintedanib and placebo, respectively. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of nintedanib in 2% of patients. Vomiting led to discontinuation of nintedanib in 1% of the patients.
- For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with nintedanib.

# Embryofetal Toxicity
- Nintedanib can cause fetal harm when administered to a pregnant woman. Nintedanib was teratogenic and embryofetocidal in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on an AUC basis at oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). If nintedanib is used during pregnancy, or if the patient becomes pregnant while taking nintedanib, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with nintedanib and to use adequate contraception during treatment and at least 3 months after the last dose of nintedanib.

# Arterial Thromboembolic Events
- Arterial thromboembolic events have been reported in patients taking nintedanib. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with nintedanib and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of nintedanib-treated patients compared to 0.4% of placebo-treated patients.
- Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

# Risk of Bleeding
- Based on the mechanism of action (VEGFR inhibition), nintedanib may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with nintedanib and in 7% of patients treated with placebo.
- Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

# Gastrointestinal Perforation
- Based on the mechanism of action, nintedanib may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with nintedanib, compared to 0 cases in the placebo-treated patients.
- Use caution when treating patients who have had recent abdominal surgery. Discontinue therapy with nintedanib in patients who develop gastrointestinal perforation. Only use nintedanib in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.
The safety of nintedanib was evaluated in over 1000 IPF patients with over 200 patients exposed to nintedanib for more than 2 years in clinical trials.
Nintedanib was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Studies 2 and 3) trials, 723 patients with IPF received nintedanib 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with nintedanib and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%).
The most frequent serious adverse reactions reported in patients treated with nintedanib, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with nintedanib, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of nintedanib-treated patients and 1.8% of placebo-treated patients.
Adverse reactions leading to permanent dose reductions were reported in 16% of nintedanib-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib was diarrhea (11%).
Adverse reactions leading to discontinuation were reported in 21% of nintedanib-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in nintedanib-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).
The most common adverse reactions with an incidence of 5% and more frequent in the nintedanib than placebo treatment group are listed in Table 1.
In addition, hypothyroidism was reported in patients treated with nintedanib, more than placebo (1.1% vs. 0.6%).
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with nintedanib may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of nintedanib. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with nintedanib.
Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. Johns wort) with nintedanib should be avoided as these drugs may decrease exposure to nintedanib.

# Anticoagulants
Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
In animal reproduction toxicity studies, nintedanib caused embryofetal deaths and teratogenic effects in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). Malformations included abnormalities in the vasculature, urogenital, and skeletal systems. Vasculature anomalies included missing or additional major blood vessels. Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified). In some fetuses, organs in the urogenital system were missing. In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day). Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

## Smokers
Smoking was associated with decreased exposure to nintedanib, which may alter the efficacy profile of nintedanib. Encourage patients to stop smoking prior to treatment with nintedanib and to avoid smoking when using nintedanib.
- Monitor patients closely for tolerability of nintedanib with coadministration of P-gp and CYP3A4 inhibitors.
- Monitor for adverse reactions and consider dose modification or discontinuation of nintedanib as needed for patients with mild hepatic impairment.
- Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
In a study in renal cell cancer patients, QT/QTc measurements were recorded and showed that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.

## Absorption
Nintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100 mg dose was 4.7% (90% CI: 3.62 to 6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
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.

## Distribution
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.

## Elimination
The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%). Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.

## Metabolism
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.

## Excretion
The major route of elimination of drug-related radioactivity after oral administration of  nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of nintedanib was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.

## Specific Populations
Age, Body Weight, and Sex
Based on population PK analysis, age and body weight were correlated with nintedanib exposure. However, their effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.
Renal Impairment
Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) was limited.
Hepatic Impairment
No dedicated PK study was conducted in patients with hepatic impairment. As nintedanib is eliminated primarily by biliary/fecal excretion (>90%), hepatic impairment is likely to increase plasma nintedanib concentrations. Clinical studies excluded patients with AST or ALT greater than 1.5 times ULN. Patients with total bilirubin greater than 1.5 times ULN were also excluded. Therefore, monitor for adverse reactions and consider dose modification or discontinuation of nintedanib as needed for patients with mild hepatic impairment.
Smokers
In the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to ex- and never-smokers. The effect is not sufficient to warrant a dose adjustment.

## Drug Interaction Studies
Potential for Nintedanib to Affect Other Drugs
Effect of nintedanib coadministration on pirfenidone AUC and Cmax was evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.
In in vitro studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2. In vitro studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and P-gp; these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in vitro.
Potential for Other Drugs to Affect Nintedanib
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon coadministration with rifampicin compared to administration of nintedanib alone.
Based on a multiple-dose study in Japanese IPF patients, exposure to nintedanib decreased to 68.3% based on AUC and to 59.2% based on Cmax upon coadministration with pirfenidone compared to administration of nintedanib alone.
Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH<3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.
In in vitro studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP. In vitro studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.
Two-year oral carcinogenicity studies of nintedanib in rats and mice have not revealed any evidence of carcinogenic potential. Nintedanib was dosed up to 10 and 30 mg/kg/day in rats and mice, respectively. These doses were less than and approximately 4 times the MRHD on a plasma drug AUC basis.
Nintedanib was negative for genotoxicity in the in vitro bacterial reverse mutation assay, the mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus assay.
In rats, nintedanib reduced female fertility at exposure levels approximately 3 times the MRHD (on an AUC basis at an oral dose of 100 mg/kg/day). Effects included increases in resorption and post-implantation loss, and a decrease in gestation index. Changes in the number and size of corpora lutea in the ovaries were observed in chronic toxicity studies in rats and mice. An increase in the number of females with resorptions only was observed at exposures approximately equal to the MRHD (on an AUC basis at an oral dose of 20 mg/kg/day). Nintedanib had no effects on male fertility in rats at exposure levels approximately 3 times the MRHD (on an AUC basis at an oral dose of 100 mg/kg/day).
Studies 2 and 3 were identical in design. Study 1 was very similar in design. Patients were randomized in a 3:2 ratio (1:1 for Study 1) to either nintedanib 150 mg or placebo twice daily for 52 weeks. Study 1 also included other treatment arms (50 mg daily, 50 mg twice daily, and 100 mg twice daily) that are not further discussed. The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). Time to first acute IPF exacerbation was a key secondary endpoint in Studies 2 and 3 and a secondary endpoint in Study 1. Change from baseline in FVC percent predicted and survival were additional secondary endpoints in all studies.
Patients were required to have a diagnosis of IPF (ATS/ERS/JRS/ALAT criteria) for 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the studies. Patients were also excluded if they received other investigational therapy, azathioprine, cyclophosphamide, or cyclosporine A within 8 weeks of entry into this trial, or n-acetyl cysteine and prednisone (>15 mg/day or equivalent) within 2 weeks. The majority of patients were Caucasian (60%) or Asian (30%) and male (79%). Patients had a mean age of 67 years and a mean FVC percent predicted of 80%.
Annual Rate of Decline in FVC 
A statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated in patients receiving nintedanib compared to patients receiving placebo based on the random coefficient regression model, adjusted for gender, height, and age. The treatment effect on FVC was consistent in all 3 studies. See Table 2 for individual study results.
Figure 1 displays the change from baseline over time in both treatment groups for Study 2. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52. Similar plots were seen for Studies 1 and 3.
Change from Baseline in Percent Predicted Forced Vital Capacity 
Figure 2 presents the cumulative distribution for all cut-offs for the change from baseline in FVC percent predicted at Week 52 for Study 2. For all categorical declines in lung function, the proportion of patients declining was lower on nintedanib than on placebo. Study 3 showed similar results.
Time to First Acute IPF Exacerbation 
Acute IPF exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest x-ray, and/or new high-resolution CT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute IPF exacerbation was adjudicated in Studies 2 and 3. In Studies 1 (investigator-reported) and 3 (adjudicated), the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving nintedanib compared to placebo (hazard ratio : 0.16, 95% CI: 0.04, 0.71) and (HR:0.20, 95% CI: 0.07, 0.56), respectively. In Study 2 (adjudicated), there was no difference between the treatment groups (HR: 0.55, 95% CI: 0.20, 1.54).
Survival 
Survival was evaluated for nintedanib compared to placebo in Studies 2 and 3 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (See Figure 3).
Bottles of 60           NDC: 0597-0145-60
- 100 mg: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100". They are packaged in HDPE bottles with a child-resistant closure, available as follows:
Bottles of 60           NDC: 0597-0143-60
NDC 0597-0145-60
NDC 0597-0143-60
OFEV 150 mg Carton
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OFEV 100 mg Label
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OFEV 100 mg Carton
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