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Erlotinib

PubChem CID
176870
Structure
Erlotinib_small.png
Erlotinib_3D_Structure.png
Molecular Formula
Synonyms
  • Erlotinib
  • 183321-74-6
  • N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
  • Tarceva
  • Erlotinib free base
Molecular Weight
393.4 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2005-03-26
  • Modify:
    2025-01-18
Description
Erlotinib is a quinazoline compound having a (3-ethynylphenyl)amino group at the 4-position and two 2-methoxyethoxy groups at the 6- and 7-positions. It has a role as an antineoplastic agent, a protein kinase inhibitor and an epidermal growth factor receptor antagonist. It is a member of quinazolines, a terminal acetylenic compound, an aromatic ether and a secondary amino compound.
Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that is used in the treatment of non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is typically marketed under the trade name Tarceva. Erlotinib binds to the epidermal growth factor receptor (EGFR) tyrosine kinase in a reversible fashion at the adenosine triphosphate (ATP) binding site of the receptor. Recent studies demonstrate that erlotinib is also a potent inhibitor of JAK2V617F, which is a mutant form of tyrosine kinase JAK2 found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. This finding introduces the potential use of erlotinib in the treatment of JAK2V617F-positive PV and other myeloproliferative disorders.
Erlotinib is a Kinase Inhibitor. The mechanism of action of erlotinib is as a Protein Kinase Inhibitor.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Erlotinib.png

1.2 3D Conformer

1.3 Crystal Structures

COD records with this CID as component

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 InChI

InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

AAKJLRGGTJKAMG-UHFFFAOYSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C22H23N3O4
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 PharmGKB ID

2.3.14 Pharos Ligand ID

2.3.15 RXCUI

2.3.16 Wikidata

2.3.17 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 11C erlotinib
  • 11C-erlotinib
  • 358,774, CP
  • 358774, CP
  • CP 358,774
  • CP 358774
  • CP-358,774
  • CP-358774
  • CP358,774
  • CP358774
  • erlotinib
  • erlotinib HCl
  • erlotinib hydrochloride
  • HCl, Erlotinib
  • Hydrochloride, Erlotinib
  • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
  • OSI 774
  • OSI-774
  • OSI774
  • Tarceva

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
393.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3-AA
Property Value
3.3
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
11
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
393.16885622 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
393.16885622 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
74.7 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
29
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
525
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Solubility

Very slightly soluble (hydrochloride salt - maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2)
8.91e-03 g/L

3.2.3 LogP

2.7
2.7

3.2.4 Other Experimental Properties

MW: 429.90. MP: 228-230 °C. pKa (25 °C): 5.42. Solubility in water (pH approx 2): approximately 0.5 mg/mL. Slightly soluble in methanol. Practically insoluble in acetonitrile, acetone, ethyl acetate /Erlotinib hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 629

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors;
Human drug -> Discontinued
Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Targeted therapies

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

Technique
GC/MS
Source of Spectrum
H.H.Maurer, M.Meyer, K.Pfleger, A.A. Weber / University of Saarland, D-66424 Homburg Germany
Copyright
Copyright © 2023-2024 Wiley-VCH GmbH. All Rights Reserved.
Thumbnail
Thumbnail

4.1.2 LC-MS

1 of 32
View All
Authors
Kevin S. Jewell; Björn Ehlig; Arne Wick
Instrument
TripleTOF 5600 SCIEX
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
40
Fragmentation Mode
CID
Column Name
Zorbax Eclipse Plus C18 2.1 mm x 150 mm, 3.5 um, Agilent
Retention Time
7.429 min
Precursor m/z
394.1761
Precursor Adduct
[M+H]+
Top 5 Peaks

278.0932 999

336.1351 737

304.1095 202

394.1775 196

276.0777 138

Thumbnail
Thumbnail
License
dl-de/by-2-0
2 of 32
View All
Authors
Kevin S. Jewell; Björn Ehlig; Arne Wick
Instrument
TripleTOF 5600 SCIEX
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
80
Fragmentation Mode
CID
Column Name
Zorbax Eclipse Plus C18 2.1 mm x 150 mm, 3.5 um, Agilent
Retention Time
7.429 min
Precursor m/z
394.1761
Precursor Adduct
[M+H]+
Top 5 Peaks

101.039 999

276.078 807

161.035 680

220.0872 654

231.0793 618

Thumbnail
Thumbnail
License
dl-de/by-2-0

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Erlotinib is indicated for: - The treatment of metastatic non-small cell lung cancer (NSCLC) with tumors showing epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. - In combination with first-line treatment for patients diagnosed with locally advanced, unresectable or metastatic pancreatic cancer. The safety and efficacy of erlotinib have not been established for patients with NSCLC whose tumors show other EGFR mutations. Additionally it is not recommended for use in combination with platinum-based chemotherapy.
Non-small cell lung cancer (NSCLC)Tarceva is also indicated for switch maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer with EGFR activating mutations and stable disease after first-line chemotherapy. Tarceva is also indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. In patients with tumours without EGFR activating mutations, Tarceva is indicated when other treatment options are not considered suitable. When prescribing Tarceva, factors associated with prolonged survival should be taken into account. No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with Epidermal Growth Factor Receptor (EGFR)-IHC - negative tumours. Pancreatic cancer Tarceva in combination with gemcitabine is indicated for the treatment of patients with metastatic pancreatic cancer . When prescribing Tarceva, factors associated with prolonged survival should be taken into account.

7.2 LiverTox Summary

Erlotinib is a tyrosine kinase receptor inhibitor that is used in the therapy of advanced or metastatic pancreatic or non-small cell lung cancer. Erlotinib therapy is associated with transient elevations in serum aminotransferase levels during therapy and rare instances of clinically apparent acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors;
Antineoplastic Agents

7.4 WHO Essential Medicines

Drug
Drug Classes
Targeted therapies
Formulation
Oral - Solid: 100 mg; 150 mg
Indication
Other specified malignant neoplasms of bronchus or lung

7.5 FDA National Drug Code Directory

7.6 Drug Labels

Drug and label
Active ingredient and drug

7.7 Cancer Drugs

Drug Name
Erlotinib Hydrochloride
Brand Name(s)
Tarceva
FDA Approved
Yes
Drug Use

Erlotinib hydrochloride is approved to be used alone or with other drugs to treat:

• Non-small cell lung cancer (NSCLC) that is metastatic and has certain EGFR gene mutations. It may be used:

• As the first therapy.

• In patients on maintenance therapy or whose disease has gotten worse after treatment with chemotherapy.

The use of erlotinib hydrochloride to treat NSCLC that does not have the EGFR gene mutations is no longer FDA-approved.

• Pancreatic cancer. It is used with gemcitabine hydrochloride in patients whose cancer cannot be removed by surgery or has spread.

Erlotinib hydrochloride is also being studied in the treatment of other types of cancer.

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.8.3 NIPH Clinical Trials Search of Japan

7.9 EMA Drug Information

Medicine
Category
Human drugs
Therapeutic area
Carcinoma, Non-Small-Cell Lung; Pancreatic Neoplasms
Active Substance
erlotinib
INN/Common name
erlotinib
Pharmacotherapeutic Classes
Antineoplastic agents
Status
This medicine is authorized for use in the European Union
Company
Roche Registration GmbH
Market Date
2005-09-19

7.10 Therapeutic Uses

Erlotinib hydrochloride monotherapy is indicated for the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
Erlotinib hydrochloride monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
Erlotinib hydrochloride in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20

7.11 Drug Warnings

The manufacturer states that there are no known contraindications to the use of erlotinib.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040
Serious, sometimes fatal, interstitial lung disease-like events have occurred in patients receiving erlotinib. Interstitial lung disease-like events have been reported in approximately 0.7% of about 4900 patients receiving erlotinib in controlled and uncontrolled studies. In the principal efficacy study for non-small cell lung cancer, the reported incidence of interstitial lung disease-like events (0.8%) was similar among patients receiving erlotinib and those receiving placebo. In the principal efficacy study for pancreatic cancer, interstitial lung disease-like events occurred in 2.5% of patients receiving erlotinib and gemcitabine versus 0.4% of those receiving placebo and gemcitabine. Onset of manifestations occurred from 5 days to more than 9 months (median: 39 days) after initiating erlotinib therapy. Reported diagnoses in patients suspected of having interstitial lung disease-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, and lung infiltration. Among patients receiving erlotinib for non-small cell lung cancer, most of these cases were associated with confounding or contributing factors, including concomitant or prior chemotherapy, prior radiotherapy, preexisting parenchymal lung disease, metastatic lung disease, or pulmonary infections.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040
Interruption or discontinuance of erlotinib therapy may be required in patients experiencing pulmonary toxicity.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040
Hepatorenal syndrome or acute renal failure, sometimes fatal, and renal insufficiency, with or without hypokalemia, have been reported in patients receiving erlotinib. Factors contributing to these adverse renal effects included baseline hepatic impairment; severe dehydration caused by diarrhea, vomiting, and/or anorexia; and concurrent chemotherapy. If dehydration occurs, erlotinib therapy should be interrupted and rehydration measures should be initiated. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040
For more Drug Warnings (Complete) data for Erlotinib (27 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 MeSH Pharmacological Classification

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

8.2 FDA Pharmacological Classification

1 of 2
FDA UNII
J4T82NDH7E
Active Moiety
ERLOTINIB
Pharmacological Classes
Established Pharmacologic Class [EPC] - Kinase Inhibitor
Pharmacological Classes
Mechanisms of Action [MoA] - Protein Kinase Inhibitors
FDA Pharmacology Summary
Erlotinib is a Kinase Inhibitor. The mechanism of action of erlotinib is as a Protein Kinase Inhibitor.
2 of 2
Non-Proprietary Name
ERLOTINIB
Pharmacological Classes
Protein Kinase Inhibitors [MoA]; Kinase Inhibitor [EPC]

8.3 ATC Code

L01EB02
S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EB - Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors

L01EB02 - Erlotinib

8.4 Absorption, Distribution and Excretion

Absorption
Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib.
Route of Elimination
Following a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound).
Volume of Distribution
Apparent volume of distribution = 232 L
Clearance
Smokers have a 24% higher rate of erlotinib clearance.
Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein. Erlotinib has an apparent volume of distribution of 232 liters.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
Time to reach steady state plasma concentration /is/ 7 - 8 days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had a 24% higher rate of erlotinib clearance.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent).
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
For more Absorption, Distribution and Excretion (Complete) data for Erlotinib (10 total), please visit the HSDB record page.

8.5 Metabolism / Metabolites

Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1.
Metabolism and excretion of erlotinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, were studied in healthy male volunteers after a single oral dose of (14)C-erlotinib hydrochloride (100-mg free base equivalent, approximately 91 microCi/subject)... In plasma, unchanged erlotinib represented the major circulating component, with the pharmacologically active metabolite M14 accounting for approximately 5% of the total circulating radioactivity. Three major biotransformation pathways of erlotinib are O-demethylation of the side chains followed by oxidation to a carboxylic acid, M11 (29.4% of dose); oxidation of the acetylene moiety to a carboxylic acid, M6 (21.0%); and hydroxylation of the aromatic ring to M16 (9.6%). In addition, O-demethylation of M6 to M2, O-demethylation of the side chains to M13 and M14, and conjugation of the oxidative metabolites with glucuronic acid (M3, M8, and M18) and sulfuric acid (M9) play a minor role in the metabolism of erlotinib. The identified metabolites accounted for >90% of the total radioactivity recovered in urine and feces. The metabolites observed in humans were similar to those found in the toxicity species, rats and dogs.
Ling J et al; Drug Metab Dispos 34 (3): 420-6 (2006)
Erlotinib has known human metabolites that include Erlotinib M14.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

8.6 Biological Half-Life

Median half-life of 36.2 hours.
A population pharmacokinetic analysis in 591 patients receiving the single-agent erlotinib hydrochloride 2nd/3rd line regimen showed a median half-life of 36.2 hours.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20

8.7 Mechanism of Action

The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.
Although the exact mechanism of antineoplastic activity of erlotinib has not been fully elucidated, erlotinib appears to inhibit the intracellular phosphorylation of tyrosine kinase associated with EGFR, which is expressed on the surface of normal and cancer cells. Specificity with regard to other tyrosine kinase receptors has not been fully characterized.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1042
Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been demonstrated to treat advanced or metastatic non-small cell lung cancer to prolong survival after failure of first-line or second-line chemotherapy. However, little is known about its effects on immune system. In the present study, /investigators/ aimed to investigate the immunosuppressive activity of erlotinib on T lymphocytes both in vitro and in vivo, and further explore its potential molecular mechanism. Erlotinib exerted a significant inhibition on the T cell proliferation and activation induced by concanavalin A, anti-CD3 plus anti-CD28, staphylococcal enterotoxin B or phorbol myristate acetate respectively in a concentration-dependent manner and it also inhibited the secretion of the proinflammatory cytokines such as IL-2 and IFN-gamma of activated T cells. Further study showed that erlotinib caused G0/G1 arrest and suppressed the phosphorylations of c-Raf, ERK and Akt in activated T cells. Moreover, erlotinib significantly ameliorated picryl chloride-induced ear contact dermatitis in a dose-dependent manner in vivo. In summary, these findings suggest that erlotinib may cause the impairment of T-cell-mediated immune response both in vitro and in vivo through inhibiting T cell proliferation and activation, which is closely associated with its potent down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.
Luo Q et al; Toxicol Appl Pharmacol 251 (2): 130-6 (2011)

8.8 Human Metabolite Information

8.8.1 Cellular Locations

  • Cytoplasm
  • Extracellular
  • Membrane

8.8.2 Metabolite Pathways

8.9 Biochemical Reactions

8.10 Transformations

9 Use and Manufacturing

9.1 Uses

MEDICATION

Use (kg; approx.) in Germany (2009): >100

Use (kg; exact) in Germany (2009): 129

Consumption (g per capita; approx.) in Germany (2009): 0.00122

Consumption (g per capita; exact) in Germany (2009): 0.00158

Calculated removal (%): 12.4

9.1.1 Use Classification

Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category

9.2 Methods of Manufacturing

Preparation: R.C. Schnur, L.D. Arnold, WO 9630347; eidem, US 5747498 (1996, 1998 both to Pfizer)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 629

9.3 Formulations / Preparations

Erlotinib Hydrochloride preparations (AHFS, 2012)

Table: Erlotinib Hydrochloride preparations

Route
Oral
Formulation
Tablet
Strength
25 mg (of erlotinib)
Brand (Manufacturer)
Tarceva (Genentech)
Route
Oral
Formulation
Tablet
Strength
100 mg (of erlotinib)
Brand (Manufacturer)
Tarceva (Genentech)
Route
Oral
Formulation
Tablet
Strength
150 mg (of erlotinib)
Brand (Manufacturer)
Tarceva (Genentech)

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1042

10 Identification

10.1 Clinical Laboratory Methods

HPLC determination in plasma
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 629

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Irritant
Health Hazard
Environmental Hazard
Signal
Warning
GHS Hazard Statements

H302 (25%): Harmful if swallowed [Warning Acute toxicity, oral]

H351 (75%): Suspected of causing cancer [Warning Carcinogenicity]

H411 (16.7%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

H413 (75%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P264, P270, P273, P280, P301+P317, P318, P330, P391, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 12 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (25%)

Carc. 2 (75%)

Aquatic Chronic 2 (16.7%)

Aquatic Chronic 4 (75%)

11.2 Accidental Release Measures

11.2.1 Cleanup Methods

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875

11.2.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
For more Disposal Methods (Complete) data for Erlotinib (8 total), please visit the HSDB record page.

11.2.3 Preventive Measures

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
For more Preventive Measures (Complete) data for Erlotinib (19 total), please visit the HSDB record page.

11.3 Handling and Storage

11.3.1 Storage Conditions

Store at 25 °C (77 °F); excursions permitted to 15 - 30 °C (59 - 86 °F).
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20

11.4 Exposure Control and Personal Protection

11.4.1 Personal Protective Equipment (PPE)

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875

11.5 Transport Information

11.5.1 Shipment Methods and Regulations

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875

11.6 Regulatory Information

11.6.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including erlotinib hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Erlotinib hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of November 21, 2012: https://www.fda.gov/cder/ob/

12 Toxicity

12.1 Toxicological Information

12.1.1 Hepatotoxicity

Elevations in serum aminotransferase levels are common during erlotinib therapy of pancreatic and lung cancers, and values above 5 times the upper limit of normal occur in at least 10% of patients. Similar rates of ALT elevations, however, can occur with comparable antineoplastic regimens. The abnormalities are usually asymptomatic and self-limited, but may require dose adjustment or discontinuation (Case 1). In addition, there have been rare reports of clinically apparent liver injury attributed to erlotinib therapy. The time to onset is typically within days or weeks of starting therapy, and the liver injury can be severe, there being at least a dozen fatal instances reported in the literature. The onset of injury can be abrupt and the pattern of serum enzyme elevations is usually hepatocellular (Case 2). Immunoallergic features (rash, fever and eosinophilia) are not common and autoantibody formation has not been reported. Routine monitoring of liver tests during therapy is recommended. The rate of clinically significant liver injury and hepatic failure is increased in patients with preexisting cirrhosis or hepatic impairment due to liver tumor burden.

Likelihood score: B (likely but uncommon cause of clinically apparent liver injury).

12.1.2 Drug Induced Liver Injury

Compound
erlotinib
DILI Annotation
Most-DILI-Concern
Severity Grade
8
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the clinical use of erlotinib during breastfeeding. Because erlotinib is 93% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 36 hours and it might accumulate in the infant. It is also given in combination with gemcitabine for pancreatic cancer, which may increase the risk to the infant. The manufacturer recommends that breastfeeding be discontinued during erlotinib therapy and for 2 weeks after the final dose.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.4 Interactions

Because cigarette smoking reduces systemic exposure to erlotinib, patients should be advised to stop smoking. If patients continue to smoke, an increase in erlotinib dosage may be considered; upon smoking cessation, dosage of erlotinib should be reduced immediately to the starting dose level.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1041
Drugs that increase the pH of the upper GI tract decrease the solubility of erlotinib and reduce its bioavailability.1 Concomitant administration of omeprazole, a proton pump inhibitor, decreased the area under the concentration-time curve for erlotinib by 46% and decreased the maximum concentration of erlotinib by 61%. Increasing the dose level of erlotinib is not likely to compensate for the loss of exposure, and separation of doses may not eliminate the interaction because proton pump inhibitors have an extended effect on the pH of the upper GI tract. If possible, the concomitant use of erlotinib and proton pump inhibitors should be avoided.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1042
The use of antacids may be considered as an alternative to histamine 2 receptor blockers or proton pump inhibitors in patients receiving erlotinib. However, the effect of antacids on the disposition of erlotinib has not been studied. If use of an antacid is necessary, the antacid dose and the erlotinib dose should be separated by several hours.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1042
Potential pharmacologic interaction (increased international normalized ratio [INR] and infrequent reports of bleeding, including GI and non-GI bleeding). Monitor prothrombin time (PT) or INR regularly in patients receiving erlotinib concomitantly with warfarin or other coumarin-derivative anticoagulants.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1042
For more Interactions (Complete) data for Erlotinib (7 total), please visit the HSDB record page.

12.1.5 Antidote and Emergency Treatment

In case of suspected overdose, erlotinib should be withheld and symptomatic treatment instituted.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

12.1.6 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ ... In the present report, unusual hematologic complications were detected after erlotinib was administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Four patients pre-treated with cisplatin or its analog-based combinations, were evaluated. Erlotinib was given at a dose of 150 mg daily. In cases of intolerable adverse reactions, the dose was either reduced to 100 mg daily or treatment was interrupted for a maximum of two weeks. Serious hematologic toxicity (or complications) developed in these 4 patients after 4-8.5 months of treatment. Two patients developed leukemias (AML, CML) and two, myelodysplastic syndrome. Whether or not these hematologic complications were related to erlotinib treatment is comprehensively discussed.
Stathopoulos GP et al; Anticancer Res 30 (3): 973-6 (2010)
/SIGNS AND SYMPTOMS/ Single oral doses of erlotinib up to 1,000 mg in healthy subjects and weekly doses up to 1,600 mg in cancer patients have been tolerated. Repeated twice-daily doses of 200 mg single-agent erlotinib in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, an unacceptable incidence of severe adverse reactions, such as diarrhea, rash, and liver transaminase elevation, may occur above the recommended dose.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
/CASE REPORTS/ ...The use of EGFR-TKI is associated with unique and dramatic dermatologic side effects. /Investigators/ report 2 patients with non small cell lung cancer developing a typical acneiform (papulo-pustular) eruption shortly after initiation of EGFR-TKI /therapy with erlotinib/.
Ong CK et al; Med J Malaysia 67 (2): 222-3 (2012)
/CASE REPORTS/ ... A 59-year-old man, who was referred to a cornea service, presented with blurred vision and pain OD. Visual acuity was 6/20. Slit-lamp examination showed a severe corneal epithelial defect and ocular inflammation OD. Eighteen months previously, he had been diagnosed with lung cancer and had been undergoing treatment with erlotinib for 6 months. He had no history of ocular surgery, trauma or diabetes. After topical antibiotic therapy was started and the erlotinib treatment was discontinued for 1 week, the corneal findings resolved completely. The visual acuity recovered to 20/20 after 8 weeks. An EGFR inhibitor used to treat lung cancer can cause severe corneal disorders including severe corneal defects and ocular inflammation. Clinicians should consider the possibility of erlotinib in cases of corneal disorders of uncertain etiology.
Hori Y et al; Nihon Ganka Gakkai Zasshi 116 (5): 510-5 (2012)
For more Human Toxicity Excerpts (Complete) data for Erlotinib (22 total), please visit the HSDB record page.

12.1.7 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Two-year carcinogenicity studies were conducted in mice and rats orally, at erlotinib doses up to 60 mg/kg/day in mice, 5 mg/kg/day in female rats, and 10 mg/kg/day in male rats. The studies were negative for carcinogenic findings. Exposure in mice at the highest dose tested was approximately 10-fold the exposure in humans at the erlotinib dose of 150 mg/day. The highest doses evaluated in rats resulted in exposures that were 2-fold of human values in male rats and similar, but slightly lower than human values in female rats.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/sq m/day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/sq m/day in the rat (0.7 times the clinical dose of 150 mg/day on a mg/sq m basis).
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Female rats treated with 30 mg/sq m/day or 60 mg/sq m/day (0.3 or 0.7 times the clinical dose, on a mg/sq m basis) of erlotinib prior to mating through the first week of pregnancy had an increase in early resorptions that resulted in a decrease in the number of live fetuses.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Erlotinib has been shown to cause maternal toxicity with associated embryofetal lethality and abortion in rabbits when given at doses that result in plasma drug concentrations of approximately 3 times those in humans (AUCs at 150 mg daily dose). When given during the period of organogenesis to achieve plasma drug concentrations approximately equal to those in humans, based on AUC, there was no increased incidence of embryofetal lethality or abortion in rabbits or rats.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
/GENOTOXICITY/ Erlotinib has been tested for genotoxicity in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration, and mammalian cell mutation) and an in vivo mouse bone marrow micronucleus test and did not cause genetic damage.
US Natl Inst Health; DailyMed. Current Medication Information for TARCEVA (erlotinib hydrochloride) tablet (April 2012). Available from, as of November 10, 2012: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20

12.1.8 Populations at Special Risk

Because erlotinib undergoes hepatic metabolism and biliary excretion, the drug should be used with caution in patients with hepatic impairment.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1041
Patients with a history of peptic ulcer disease or diverticulitis and those who are receiving concomitant therapy with antiangiogenesis drugs, corticosteroids, nonsteroidal anti-inflammatory agents (NSAIAs), and/or taxane-based chemotherapy are at increased risk for perforation while receiving erlotinib therapy.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1040
Because cigarette smoking reduces systemic exposure to erlotinib, patients should be advised to stop smoking. If patients continue to smoke, an increase in erlotinib dosage may be considered; upon smoking cessation, dosage of erlotinib should be reduced immediately to the starting dose level.
American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 1041

12.1.9 Protein Binding

93% protein bound to albumin and alpha-1 acid glycoprotein (AAG)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Nature Journal References

14.7 Chemical Co-Occurrences in Literature

14.8 Chemical-Gene Co-Occurrences in Literature

14.9 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of erlotinib.
  • Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of erlotinib.
  • Take on an empty stomach. Food increases erlotinib bioavailability, therefore administer at least 1 hour before or 2 hours after meals.

16.5 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 KEGG: Target-based Classification of Drugs

18.6 KEGG: Drug Groups

18.7 WHO ATC Classification System

18.8 FDA Pharm Classes

18.9 ChemIDplus

18.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.11 ChEMBL Target Tree

18.12 UN GHS Classification

18.13 NORMAN Suspect List Exchange Classification

18.14 EPA DSSTox Classification

18.15 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
  2. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  5. Therapeutic Target Database (TTD)
  6. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  7. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  8. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  9. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    4-[(3-Ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline
    https://echa.europa.eu/substance-information/-/substanceinfo/100.216.020
    4-[(3-Ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline (EC: 689-196-2)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/221278
  10. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  11. Hazardous Substances Data Bank (HSDB)
  12. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  13. ChEBI
  14. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  15. LiverTox
  16. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  17. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  18. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  19. ClinicalTrials.gov
    LICENSE
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  20. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  21. DailyMed
  22. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  23. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  24. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    ERLOTINIB
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  25. Drugs and Lactation Database (LactMed)
  26. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  27. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  28. EU Clinical Trials Register
  29. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  30. National Drug Code (NDC) Directory
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    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  31. Japan Chemical Substance Dictionary (Nikkaji)
  32. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  33. MassBank Europe
  34. Metabolomics Workbench
  35. Nature Chemical Biology
  36. NCI Cancer Drugs
  37. NIPH Clinical Trials Search of Japan
  38. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  39. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  40. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  41. Protein Data Bank in Europe (PDBe)
  42. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
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    https://www.rcsb.org/pages/policies
  43. SpectraBase
  44. Springer Nature
  45. Thieme Chemistry
    LICENSE
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
  46. Wikidata
  47. Wikipedia
  48. Wiley
  49. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
  50. PubChem
  51. GHS Classification (UNECE)
  52. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  53. PATENTSCOPE (WIPO)
  54. NCBI
CONTENTS