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erlotinib
Erlotinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor. Activation of epidermal growth factor receptors (EGFR) results in a cascade of intracellular signalling events, leading to cell proliferation, differentiation, cell survival, angiogenesis, and invasion/metastases. These receptors are overexpressed, or mutated with constitutive activation, in NSCLC and other tumor types, and may be correlated with more aggressive tumor activity and poor clinical outcome. Continued cigarette smoking significantly reduces exposure. The safety and efficacy of higher doses in such patients has not been established.
| Bioavailability | oral : 60% (↑ with food) |
Peak plasma levels of erlotinib occur 4 hours after an oral dose in cancer patients. Steady state is achieved in 7-8 days.
| Cross blood brain barrier? | yes |
| PPB | 95% (albumin and AAG) |
Hepatic primarily via CYP3A4, and to a lesser extent via CYP1A2 and the extrahepatic isoform CYP1A1.
| Active metabolites | Yes (primarily OSI-420). |
| Inactive metabolites | Unknown |
Excretion is predominantly via the feces (>90%).
| Urine | < 9% (< 1% unchanged) |
| Half-life | (mean) : 36.2 hours |
- Non-small cell lung cancer (NSCLC)
Refer to the product monograph for a full list of approved indications.
Other Uses:
- Vulvar cancer
- Head and neck cancer
Emetogenic Potential:
Extravasation Potential: Not applicable
The following table contains adverse effects reported in the BR21 trial where the incidence was greater than placebo, or severe events from other trials.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Venous thromboembolism (4%) | E | |||
| Dermatological | Abnormal eyelash growth | D | |||
| Nail disorder (16%) (including paronychia) | E | ||||
| Photosensitivity (phototoxicity; radiation induced) | E | ||||
| Rash (75%) (or acne; may be severe) | E | ||||
| Skin discolouration (<1%) | E | ||||
| Gastrointestinal | Abdominal pain (11%) | E | |||
| Anorexia, weight loss (52%) | E | ||||
| Diarrhea (54%) (grade 3: 4%) | E | ||||
| GI hemorrhage (2%) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (17%) | E | ||||
| Nausea, vomiting (33%) | E | ||||
| General | Fatigue (52%) | E | |||
| Hematological | Hemolysis (rare) | E | |||
| Myelosuppression (11%) (usually mild) | E | ||||
| Hepatobiliary | ↑ LFTs (6%) (may be severe) | E | |||
| Infection | Infection (24%) | E | |||
| Musculoskeletal | ↑CPK (rhabdomyolysis with statins) | E | |||
| Ophthalmic | Conjunctivitis (12%) /uveitis | D | |||
| Corneal disorder (12%) (ulcer/perforation) | D | ||||
| Renal | Nephrotoxicity (may be severe) | E | |||
| Respiratory | Cough, dyspnea (45%) | E D | |||
| Pneumonitis (1%) /fibrosis | E D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Refer to protocol by which patient is being treated. EGFR mutation-positive status must be confirmed with a validated test prior to staring erlotinib therapy for first line and maintenance settings.
The recommended daily dose of erlotinib is 150 mg taken at least one hour before or two hours after the ingestion of food.
Dose levels 150mg, 100mg, 50 mg
|
Toxicity
|
Action
|
|
Manage with loperamide. If severe, associated with dehydration or unresponsive to loperamide, hold and/or reduce dose.
|
|
Hold or discontinue |
|
Hold; investigate and treat appropriately.
Discontinue if ILD confirmed
|
|
Discontinue; treat patient appropriately
|
|
Reduce by one dose level especially if being administered with potent CYP3 A4 inhibitors
|
Use with caution in combination with other hepatotoxic drugs.
|
Hepatic Impairment |
Bilirubin |
|
Transaminases |
Action |
|
Mild |
< 1.5 x ULN |
and |
1 - 2.5 x ULN |
100%, caution |
|
Moderate |
1.5 - 3 x ULN |
and/or |
2.5 - 5 x ULN |
Caution; consider ↓. If worsens, hold then ↓ 50% or discontinue |
|
Severe |
> 3 x ULN (or 2 x baseline values) |
or |
> 5 x ULN (or 3 x baseline values) |
Do not treat |
Not significantly renally excreted. No dose adjustment required if no concomitant hepatic dysfunction (Miller et al).
No adjustment required.
Safety and efficacy not established.
- Oral self-administration; drug available by outpatient prescription.
- Should be administered at least one hour before or two hours after a meal.
- patients who have a hypersensitivity to this drug or any of its components
- Erlotinib has not been studied in patients with severe hepatic or renal impairment.
- The concomitant use with potent inducers of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g. rifabutin, rifampin, rifapentin, phenytoin, carbamazepine, phenobarbital, St. John's wort), PPIs and statins should be avoided. (See Interactions).
- Patients on oral anticoagulants should be closely monitored when doses of erlotinib are started, modified or discontinued.
- Contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption
-
Mutagenicity:
Unlikely
-
Clastogenicity:
Unlikely
-
Teratogenicity:
Unlikely
-
Fetotoxicity:
Documented in animals
Erlotinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 2 weeks after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose.
-
Fertility effects:
Unlikely
Erlotinib is metabolized by CYP3A4 and to a lesser extent by CYP1A2 and is therefore susceptible to drug interactions with inducers and inhibitors of these isoenzymes.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ Erlotinib plasma concentration and decreased efficacy | ↑ metabolism of erlotinib, effects on CYP3A4 | Avoid concomitant administration of potent inducers |
| Potent CYP3A4 ± CYP1A2 inhibitors (e.g. diltiazem, ritonavir, ketoconazole, erythromycin, protease inhibitors, ciprofloxacin, grapefruit juice, etc.) | ↑ Erlotinib plasma concentration and increased toxicity | ↓ metabolism of erlotinib, effects on CYP3A4 | Avoid concomitant administration, decrease erlotinib dose with severe toxicity |
| Warfarin | ↑ anticoagulant effect | Competes for CYP3A4/A5 binding sites | Caution, monitor INR closely |
| Drugs that increase gastric pH (Proton pump inhibitors, H2-antagonists, antacids) | ↓ erlotinib exposure (AUC, Cmax) | Solubility of erlotinib decreases as pH increases | Avoid concomitant usage; consider using H2-antagonist (take erlotinib 2 h prior to AM dose or 10 h after PM dose) |
| Statins (e.g., atorvastatin, pravastatin, simvastatin, etc.) | ↑ statin-induced myopathy (including rhabdomyolysis) | Monitor liver function tests in patients with liver impairment | |
| Cigarette smoking | ↓ erlotinib exposure (by 50-60%) | ↑ clearance via CYP1A2 induction | Encourage smoking cessation |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
| Renal function tests, including electrolytes | Baseline and routine |
| Close monitoring of INR, in patients on warfarin | Especially initially, or when dose modified, held, or discontinued |
| Liver function tests | Baseline and routine, monitor closely if abnormal. |
Clinical assessments and grading of diarrhea, skin/nails, stomatitis, thromboembolism, infection, eye symptoms and respiratory symptoms. |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- erlotinib - Incurable progressive NSCLC, with specific criteria
Adjei AA: Epidermal growth factor receptor tyrosine kinase inhibitors in cancer therapy. Drug Future 2001; 26(11):1087.
E- American Society of Health-System Pharmacists. 2005: Erlotinib.
Herbst RS, Prager D, Hermann R et al. TRIBUTE - A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2005; 23(25): 5892-9.
Hidalgo M, Siu LL, Nemunaitis J et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001; 19(13): 3267-3279.
Erlotinib: e-Drugdex Evaluations. Micromedex Healthcare Series.
Jatoi A, Rowland A, Sloan JA, et al. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the north central cancer treatment group (N03CB). Cancer 2008; 113:847–53.
Micromedex review: Erlotinib
Micromedex P&T Quick Report: Erlotinib.
Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101. J Clin Oncol 2007; 25: 3055-60.
Product monograph: Tarceva® (erlotinib). Hoffman-La Roche Ltd, Canada, March 2017.
Prescribing information: Tarceva® (erlotinib). Genentech Inc. U.S., April 2009.
Shepherd F, Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non–small-cell lung cancer. NEJM 2005; 353(2): 123-132.
Vogelbaum MA, Peereboom D, Stevens GH, et al. Phase II study of single agent therapy with the EGFR tyrosine kinase inhibitor erlotinib in recurrent glioblastoma multiforme. Proceedings from the 29th ESMO Congress, Vienna, Austria, October 29 – November 3, 2004; (Abstract #783).
October 2022 Updated Indications, Pregnancy/lactation sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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