Nintedanib (Monograph)

Brand name: Ofev
Drug class: Antifibrotic Agents

Medically reviewed by Drugs.com on Jun 22, 2023. Written by ASHP.

Introduction

An inhibitor of multiple tyrosine kinases; reduces fibroblast activity in idiopathic pulmonary fibrosis (IPF).

Uses for Nintedanib

Idiopathic Pulmonary Fibrosis

Treatment of idiopathic pulmonary fibrosis (IPF) in adults (designated an orphan drug by FDA for this use). Guidelines generally recommend nintedanib or pirfenidone in patients with a diagnosis of IPF.

Chronic Fibrosing Interstitial Lung Diseases

Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype in adults. Guidelines generally suggest nintedanib for progressive pulmonary fibrosis in patients who did not respond to standard management for fibrotic ILD other than IPF, based on low quality evidence.

Systemic Sclerosis-associated Interstitial Lung Disease

Slowing the decline in pulmonary function in patients with systemic sclerosis-associated ILD in adults (designated an orphan drug by FDA for this use). Guidelines recommend additional research on the efficacy and safety of nintedanib in patients with non-IPF ILD manifesting progressive pulmonary fibrosis.

Nintedanib Dosage and Administration

General

Pretreatment Screening

Conduct liver function tests prior to initiation of therapy.
Perform a pregnancy test in females of reproductive potential prior to initiation of therapy.

Patient Monitoring

Liver function tests should be performed at regular intervals for the first 3 months, then every 3 months, and as clinically indicated. Measure liver tests in patients with symptoms of liver injury such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Monitor for the development of adverse GI effects and treat as necessary with appropriate therapy (e.g., antidiarrheal agents, antiemetics, fluid replacement).
Since nintedanib may increase the risk of bleeding, monitor patients closely receiving anticoagulation therapy, and adjust anticoagulation treatment as necessary.

Administration

Oral Administration

Administer orally twice daily (approximately 12 hours apart) with food.

Swallow capsules whole with liquid; do not chew or crush.

If a dose is missed, take the next dose at the regularly scheduled time. Do not double the dose or take extra doses.

Dosage

Available as nintedanib esylate; dosage expressed in terms of nintedanib.

Adults

Idiopathic Pulmonary Fibrosis

Oral

150 mg twice daily.

Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype

Oral

150 mg twice daily.

Systemic Sclerosis-Associated Interstitial Lung Disease

Oral

150 mg twice daily.

Dosage Modification for Toxicity

Hepatic Toxicity

Mild hepatic impairment (Child Pugh A): 100 mg twice daily approximately 12 hours apart. Not recommended in patients with moderate or severe hepatic impairment.

ALT or AST elevations >3 times but <5 times the ULN without signs or symptoms of severe liver damage: Temporarily interrupt therapy or reduce dosage to 100 mg twice daily. When liver function tests return to baseline values, may resume nintedanib at 100 mg twice daily and may subsequently increase dosage to 150 mg twice daily.

ALT or AST elevations >5 times the ULN, or >3 times the ULN with signs or symptoms of severe liver damage: Discontinue therapy.

Other Adverse Effects

If adverse reactions occur and are intolerable, despite symptomatic treatment, temporarily interrupt therapy or reduce dosage to 100 mg twice daily until the adverse reaction improves or resolves.

May resume nintedanib 150 mg twice daily; alternatively, initially reduce dosage to 100 mg twice daily and may subsequently increase dosage to 150 mg twice daily.

Discontinue therapy if intolerable adverse reactions occur or persist at a dosage of 100 mg twice daily.

Prescribing Limits

Adults

Oral

300 mg daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child Pugh A): 100 mg twice daily approximately 12 hours apart. Not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment.

Renal Impairment

No initial dosage adjustment required in patients with mild to moderate renal impairment (Cl_cr 30–90 mL/minute).

Not studied in patients with severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Nintedanib

Contraindications

None.

Warnings/Precautions

Hepatic Toxicity

Use of nintedanib is not recommended in patients with moderate or severe hepatic impairment (Child Pugh class B or C). Use a lower dose in patients with mild hepatic impairment (Child Pugh class A).

Serious, including fatal cases, and non-serious cases of drug-induced liver injury (DILI) have occurred with nintedanib in clinical trials and postmarketing studies. Most hepatic events occur within the first 3 months of therapy. Abnormal liver function test results reported. If hepatic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Perform liver function tests prior to initiation, at regular intervals for the first 3 months, then periodically thereafter or as clinically indicated. Measure liver enzymes promptly in those with symptoms of liver dysfunction, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

GI Effects

Diarrhea, nausea, and vomiting may occur. In clinical studies, diarrhea reported frequently in patients receiving nintedanib and generally occurred within first 3 months of therapy. Nausea and vomiting reported less frequently.

Treat adverse GI effects as necessary with appropriate supportive therapy. If diarrhea occurs or if nausea or vomiting persists despite appropriate supportive care, temporary interruption and/or dosage reduction may be necessary.

Discontinue nintedanib if diarrhea persists despite symptomatic treatment or if severe nausea or vomiting does not resolve.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals. Avoid pregnancy during therapy and for at least 3 months after drug discontinuance. Advise pregnant women of the potential fetal hazard.

Arterial Thromboembolic Events

Arterial thromboembolic events (e.g., MI) reported. Use with caution in patients with cardiovascular risks, including coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

Risk of Bleeding

May increase the risk of bleeding based on mechanism of action. Use in patients with risk factors for bleeding only if the potential benefit outweighs the risk.

GI Perforation

May increase the risk of GI perforation based on mechanism of action. Use caution in patients with recent abdominal surgery, history of diverticular disease, or receiving corticosteroids or NSAIAs concurrently. Use in patients with risk factors for GI perforation only if the potential benefit outweighs the risk. Discontinue nintedanib if GI perforation develops.

Nephrotic Range Proteinuria

Reports of proteinuria within the nephrotic range in the postmarketing period. Available histological findings were consistent with glomerular microangiopathy with or without renal thrombi. Nintedanib discontinuation has led to improvements in proteinuria; however, residual proteinuria has occurred in some cases. Consider treatment discontinuation in patients who develop new or worsening proteinuria.

Specific Populations

Pregnancy

May cause fetal harm based on animal studies and its mechanism of action.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Breastfeeding is not recommended during treatment.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Pharmacokinetic studies in patients with Child Pugh A and Child Pugh B hepatic impairment have found increased nintedanib exposure. A dose reduction is recommended in Child Pugh A impairment, and also treatment interruption or possible drug discontinuation in patients with adverse reactions.

Renal Impairment

Systemic exposure to nintedanib not affected by mild or moderate renal impairment (Cl_cr 30–90 mL/minute); no initial dosage adjustment necessary. Safety and efficacy not established in patients with severe renal impairment or end-stage renal disease.

Common Adverse Effects

Diarrhea, nausea, abdominal pain, vomiting, elevated concentrations of hepatic enzymes (e.g., ALT, AST, alkaline phosphatase), decreased appetite, headache, decreased weight, hypertension.

Drug Interactions

Substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4.

Does not inhibit or induce CYP isoenzymes in vitro.

Has weak potential to inhibit P-gp, organic cation transporter (OCT) 1, and breast cancer resistance protein (BCRP); clinically important interaction unlikely.

Does not inhibit organic anion-transporting polypeptides (OATP) 1B1, OATP1B3, OATP2B1, OCT2, or multidrug resistance protein (MRP) 2 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes and the P-glycoprotein (P-gp) Transport System

Inhibitors of both P-gp and CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure of nintedanib). Monitor closely and reduce dosage or temporarily interrupt therapy if not tolerated.

Inducers of P-gp and CYP3A4: Potential pharmacokinetic interaction (decreased systemic exposure of nintedanib). Avoid concomitant use.

Specific Drugs

Drug	Interaction	Comments
Anticoagulants	Potential increased risk of bleeding	Monitor patients receiving full-dose anticoagulation; dosage adjustment of anticoagulant may be necessary
Antifungals, azoles (e.g., ketoconazole)	Possible increased nintedanib concentrations with P-gp and CYP3A4 inhibitors Ketoconazole increased peak concentrations and AUC of nintedanib by 1.8- and 1.6-fold, respectively	Monitor closely; reduce dosage or temporarily interrupt nintedanib therapy if not tolerated
Antimycobacterials, rifamycins (e.g., rifampin)	Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers Rifampin decreased nintedanib exposure by 50%	Avoid concomitant use
Bosentan	No effect on pharmacokinetics of nintedanib
Carbamazepine	Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers	Avoid concomitant use
Cigarette smoking	Decreased nintedanib exposure	Dosage adjustment not necessary; encourage smoking cessation
Erythromycin	Possible increased nintedanib concentrations with P-gp and CYP3A4 inhibitors	Monitor closely; reduce dosage or temporarily interrupt nintedanib therapy if not tolerated
Oral Hormonal Contraceptives	Use of nintedanib did not alter exposure to oral contraceptives containing ethinylestradiol and levonorgestrel. However, vomiting and diarrhea may reduce drug absorption.
Phenytoin	Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers	Avoid concomitant use
Pirfenidone	No effect on pirfenidone or nintedanib exposure
St. John's wort (Hypericum perforatum)	Possible decreased nintedanib concentrations with P-gp and CYP3A4 inducers	Avoid concomitant use

Nintedanib Pharmacokinetics

Absorption

Bioavailability

Exhibits dose-proportional pharmacokinetics following oral administration of 50–450 mg once daily and 150–300 mg twice daily.

Peak plasma concentrations attained within 2–4 hours after oral administration with food.

Steady-state concentrations achieved within 1 week.

Absolute oral bioavailability of a 100 mg dose of nintedanib is 4.7%.

Food

Administration with food increases systemic exposure by 20% and delays absorption by approximately 2 hours compared with fasting state.

Special Populations

Not studied in hepatic impairment; hepatic impairment expected to increase plasma nintedanib concentrations.

Mild or moderate renal impairment (Cl_cr 30–90 mL/minute) does not affect exposure to nintedanib. Not studied in severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease.

Distribution

Extent

Not known whether nintedanib is distributed into breast milk.

Plasma Protein Binding

97.8% (mainly albumin).

Elimination

Metabolism

Principally metabolized by esterases to the carboxylate metabolite, BIBF 1202, which then undergoes glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 1A1, 1A7, 1A8, and 1A10; CYP isoenzymes, mainly CYP3A4, play a minor role.

Elimination Route

Eliminated in feces (93.4%) and urine (0.65%).

Half-life

9.5 hours.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C). Protect from excessive humidity and heat.

Actions

Inhibits several receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, VEGFR-3; fibroblast growth factor receptors (FGFR)-1, FGFR-2, FGFR-3; and platelet-derived growth factor receptors (PDGFR)-α, PDGFR-β.
VEGFR, FGFR, and PDGFR signaling pathways involved in proliferation, migration, and differentiation of fibroblasts in the lungs; these kinases implicated in pathogenesis of IPF. Inhibition of these receptors reduces fibroblast activity in IPF.
Also inhibits Fms-like tyrosine kinase (FLT)-3, and nonreceptor tyrosine kinases Lck, Lyn, and Src; inhibitory effect of these kinases in IPF unknown.

Advice to Patients

Importance of reading the manufacturer’s patient information prior to beginning nintedanib therapy and each time the prescription is refilled.
Importance of taking nintedanib with food. Importance of swallowing capsules whole with liquid and not to chew or crush the capsules. Importance of washing hands if contact with the capsule contents occurs.
If a dose of nintedanib is missed, the missed dose should be skipped and the next dose taken at the regularly scheduled time; the dose should not be doubled to make up for a missed dose.
Risk of hepatotoxicity and importance of periodic liver function test monitoring. Importance of immediately reporting any manifestations of hepatotoxicity (e.g., jaundice, unusually dark or “tea-colored” urine, right upper quadrant pain, bleeding or bruising more easily than normal, lethargy, loss of appetite) to clinician.
Importance of clinician informing patients that diarrhea, nausea, and vomiting are the most common adverse effects associated with nintedanib therapy, and that the clinician may recommend supportive treatment (e.g., hydration, antidiarrhea agents, and/or antiemetics). Importance of informing clinician at first sign of diarrhea or if severe or persistent diarrhea, nausea, or vomiting occurs.
Risk of arterial thromboembolic events. Importance of advising patients to seek emergency help and to contact clinician if any symptoms suggestive of acute myocardial ischemia or other thromboembolic event occur (e.g., chest pain or pressure; arm, back, neck, or jaw pain; shortness of breath; numbness or weakness on one side of the body; trouble talking; headache; or dizziness).
Risk of GI perforation; importance of immediately informing clinician of any manifestations of GI perforation (e.g., abdominal pain or swelling).
Increased risk of bleeding. Importance of promptly informing clinician of any unusual bleeding.
Risk of fetal harm. Necessity of females of childbearing potential to avoid pregnancy and to use highly effective methods of contraception at the start of and while receiving nintedanib and for at least 3 months after the drug is discontinued. Importance of patients informing their clinicians if they are pregnant or think they may be pregnant. If females are taking oral hormonal contraceptives and experience nausea, diarrhea, or other conditions reducing the absorption of the drug, instruct patient to contact their healthcare provider for alternative highly effective contraception.
Importance of reporting signs and symptoms of nephrotic range proteinuria (e.g., fluid retention, foamy urine).
Importance of advising females to avoid breast-feeding while receiving nintedanib therapy.
Importance of stopping smoking prior to and with treatment of nintedanib.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., anticoagulants, aspirin, laxatives, St. John's wort [Hypericum perforatum]), as well as any concomitant illnesses (e.g., hepatic impairment, cardiovascular disease).
Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of nintedanib esylate is restricted.