Nintedanib

L01X - Other antineoplastic agents ATC L01XE31 Small molecule approved 2014 Oral First-in-class Natural product

JFDA label: Ofev 100 mg

Mechanism of Action

Inhibits multiple receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (nRTKs), including platelet-derived growth factor (PDGFR alpha and PDGFR beta); fibroblast growth factor receptor (FGFR1, FGFR2, FGFR3); vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3); and Fms-like tyrosine kinase-3 (FLT3). 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.

Indications

Approved

Idiopathic pulmonary fibrosis

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to nintedanib, peanut, or soya or any component of the formulation Absolute
There are no contraindications listed in the manufacturer's labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (3)

Common arterial thrombosis · Hypertension · myocardial infarction

Nervous system disorders (1)

Common Headache

Hepatobiliary disorders (1)

Very Common Increased liver enzymes

Blood and lymphatic system disorders (1)

Common Hemorrhage

Metabolism and nutrition disorders (2)

Common hypothyroidism · Weight loss

Gastrointestinal disorders (5)

Very Common abdominal pain · decreased appetite · Diarrhea · nausea · vomiting

Respiratory, thoracic and mediastinal disorders (1)

Common Bronchitis

Dosing

Source: Lexicomp

Idiopathic pulmonary fibrosis (IPF): Oral: 150 mg every 12 hours (maximum: 300 mg/day) Missed dose: If a dose is missed, the next dose should be taken at the next scheduled time. Do not make up a missed dose.

Refer to adult dosing.

CrCl ≥30 mL/minute: No initial dosage adjustment necessary. CrCl ESRD: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatic impairment at baseline: Mild impairment (Child-Pugh class A): 100 mg every 12 hours. If a patient does not tolerate 100 mg every 12 hours, consider treatment interruption or discontinue treatment to manage adverse reactions. Moderate to severe impairment (Child-Pugh class B or C): Use is not recommended (exposure is increased in moderate impairment; has not been studied in severe impairment). Hepatotoxicity during treatment: AST or ALT >3 times to AST or ALT >5 times ULN or >3 times ULN with signs or symptoms of liver damage: Discontinue therapy.

Warnings & Precautions

Source: Lexicomp

Bleeding

May increase the risk of bleeding. Use in patients with known risk of bleeding only if the benefit outweighs the risk. Serious and nonserious bleeding events (some fatal) have been reported during postmarketing.

Cardiovascular effects

Arterial thromboembolic events, including MI, have been reported. Use caution in patients at high cardiovascular risk, including in patients with known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

GI effects

Diarrhea, nausea, and vomiting may occur. Diarrhea occurred in over 50% of nintedanib-treated patients, and was generally of mild to moderate intensity and occurred within the first 3 months of treatment. Treat with appropriate supportive care (eg, adequate hydration, antidiarrheals, antiemetics); dose reduction and/or treatment interruption may be required. If GI effects do not resolve, discontinue treatment. In addition, nintedanib may increase the risk of GI perforation; cases of GI perforation (some fatal) have been reported during postmarketing. Use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or who are receiving concomitant corticosteroids or NSAIDs; only use in patients at risk of perforation if the benefit outweighs the risk. It has been recommended to wait at least 4 weeks following abdominal surgery before initiating therapy (OFEV Canadian product labeling 2017). Discontinue if perforation develops.

Hepatic effects

Serious and nonserious cases of drug-induced liver injury (including severe liver injury with fatal outcome) have been reported. Hepatic effects usually occurred within the first 3 months of treatment. Elevations of ALT, AST, GGT, alkaline phosphatase, and bilirubin were usually reversible with dose modification or interruption. Risk may be increased in patients with a low body weight ( Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Hepatic impairment

Nintedanib is primarily eliminated through biliary/fecal excretion; use is not recommended in patients with moderate or severe hepatic impairment. Dose reduction is recommended in patients with mild impairment; if adverse reactions occur, consider treatment interruption or discontinuation.

Smokers

Smoking may decrease exposure to nintedanib; patients should stop smoking prior to treatment and avoid smoking during therapy.

Pregnancy & Lactation

Pregnancy

Based on the mechanism of action and adverse events observed in animal reproduction studies, nintedanib may be expected to cause fetal harm if used during pregnancy. Women of reproductive potential should use adequate contraception during therapy; pregnancy status should be obtained before treatment and pregnancy should be avoided; effective contraception should be used during therapy and for at least 3 months after the last dose. Based on animal studies, nintedanib may reduce female fertility.

Lactation

Avoid

It is not known if nintedanib is present in breast milk. Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	Obtain liver function tests prior to initiation of treatment, at regular intervals during the first 3 months of treatment, and periodically thereafter or as clinically indicated; obtain pregnancy test prior to treatment. Monitor for GI events (eg, diarrhea, nausea, vomiting), arterial thromboembolic events, bleeding, and GI perforation.

Chemistry & Properties

Formula	C31H33N5O4
Molecular weight	539.64 g/mol
IUPAC name	methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate
CAS	656247-17-5
PubChem CID	135423438
InChIKey	`XZXHXSATPCNXJR-ZIADKAODSA-N`
logP	3.62 (XLogP 4.3)
Polar surface area	94.22 Å²
H-bond acceptors / donors	7 / 2
Drug-likeness (QED)	0.35
Lipinski violations	1

SMILES

COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—

Receptor binding (top 9)

Target	Action	Affinity
fms related receptor tyrosine kinase 4 (FLT4)	Inhibitor	pIC50 7.9
kinase insert domain receptor (KDR)	Inhibitor	pIC50 7.7
fms related receptor tyrosine kinase 1 (FLT1)	Inhibitor	pIC50 7.5
fibroblast growth factor receptor 2 (FGFR2)	Inhibitor	pIC50 7.4
platelet derived growth factor receptor alpha (PDGFRA)	Inhibitor	pIC50 7.2
platelet derived growth factor receptor beta (PDGFRB)	Inhibitor	pIC50 7.2
fibroblast growth factor receptor 1 (FGFR1)	Inhibitor	pIC50 7.2
fibroblast growth factor receptor 3 (FGFR3)	Inhibitor	pIC50 7.0
fibroblast growth factor receptor 4 (FGFR4)	Inhibitor	pIC50 6.2

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OCT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Carbamazepine	major
Dexamethasone	major
Drotrecogin alfa	major
Fosphenytoin	major
Leflunomide	major
Lomitapide	major
Lorlatinib	major
Lumacaftor	major
Mipomersen	major
Mitotane	major
Pexidartinib	major
Phenobarbital	major
Phenytoin	major
Primidone	major
Rifampicin	major
St. John's Wort	major
Teriflunomide	major
Tipranavir	major
Abametapir (topical)	moderate
Abciximab	moderate
Abiraterone	moderate
Acetylsalicylic acid	moderate
Alpelisib	moderate
Alteplase	moderate
Amiodarone	moderate
Anagrelide	moderate
Anisindione	moderate
Anistreplase	moderate
Antithrombin Alfa	moderate
Antithrombin III human	moderate
Apalutamide	moderate
Apixaban	moderate
Ardeparin	moderate
Argatroban	moderate
Asparaginase Erwinia chrysanthemi	moderate
Asparaginase Escherichia coli	moderate
Atazanavir	moderate
Bedaquiline	moderate
Bepridil	moderate
Betrixaban	moderate

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Ofev	Capsule 100 mg	60 cap	The Jordan Drugstore Co	—
Ofev	Capsule 150 mg	60 cap	The Jordan Drugstore Co	—