erlotinib (Tarceva)

Dosing and uses of Tarceva (erlotinib)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 25mg
• 100mg
• 150mg

 

Non-Small Cell Lung Cancer

Indicated for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line, maintenance, or ≥second-line treatment after progression following at least 1 prior chemotherapy regimen

150 mg PO qDay 1 hr before or 2 hrs after meals

Continue until disease progression or unacceptable toxicity

NSCLC limitations of use

• Not recommended for use in combination with platinum-based chemotherapy
• Safety and efficacy has not been evaluated as first-line treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution

 

Pancreatic Cancer

Indicated for first-line treatment in patients with locally advanced, unresectable, or metastatic pancreatic cancer

100 mg/day PO with gemcitabine

Continue until disease progression or unacceptable toxicity

Continue until disease progression or unacceptable toxicity

 

Malignant Gliomas (Orphan)

Orphan sponsor: Genentech, Inc; 1 DNA Way; South San Francisco, CA 94080-4990

 

Dosage modifications

Decrease dose by 50 mg decrements

• Strong CYP3A4 inhibitors: Reduce by 50 mg decrements if severe reactions occur when coadministered with strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, or grapefruit or grapefruit juice)
• CYP3A4 and CYP1A2 inhibitors: Avoid concomitant use if possible when coadministered with an inhibitor of both CYP3A4 and CYP1A2 (eg, ciprofloxacin)
• When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤1

Increase dose by 50 mg increments

• CYP3A4 inducers: Increase by 50 mg increments at 2 week intervals as tolerated to a maximum of 450 mg for concomitant use with CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s Wort); if possible, avoid concomitant use
• Concurrent cigarette smoking: Increase by 50 mg increments at 2 week intervals to a maximum of 300 mg; immediately reduce dose to recommended dose (ie, 100 mg or 150 mg daily) upon smoking cessation

Drugs affecting gastric pH

• Proton pump inhibitors: Avoid coadministration if possible
• H2-antagonists: Take erlotinib 10 hr after or at least 2 hr before H2-anagonist
• Antacids: Separate erlotinib and antacid doses by several hours

Discontinue erlotinib for

• Interstitial lung disease (ILD) Severe hepatic toxicity that is unimproved or does not resolve
• GI perforation
• Severe bullous, blistering, or exfoliating skin conditions
• Corneal perforation or severe ulceration

Withhold erlotiniB

• During diagnostic evaluation for ILD
• Severe renal toxicity (grades 3-4)
• Total bilirubin levels >3 xULN or transaminases >5 xULN in patients without pre-existing hepatic impairment
• In patients with pre-existing hepatic impairment for bilirubin 2 xULN or transaminases 3 xULN
• Persistent severe diarrhea or rash unresponsive to medical management
• Keratitis (grades 3-4, or grade 2 for >2 wk)
• Acute/worsening ocular disorders

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Tarceva (erlotinib) adverse (side) effects

>10%

Rash (75-76%)

Anorexia (52-69%)

Diarrhea (54-55%)

Fatigue (52-79%)

Nausea (33-40%)

Infection (39%)

Vomiting (23-25%)

Dyspnea (24%)

Stomatitis (17-19%)

Cough (16%)

Pruritus (13%)

Conjunctivitis (12%)

Dry skin (12%)

Keratoconjunctivitis sicca (12%)

Abdominal pain (11%)

 

1-10%

Elevated LFT's (grade 2)

Acne

Paronychia

Weight loss

Pneumonitis pulmonary infiltrate

Pulmonary fibrosis

 

<1%

Interstitial lung disease-like events

 

Postmarketing Reports

Musculoskeletal and connective tissue disorders: Myopathy, including rhabdomyolysis, in combination with statin therapy

Eye disorders: Ocular inflammation including uveitis

 

Warnings

Contraindications

None

 

Cautions

Risk of potentially fatal interstitial lung disease (ILD); withhold therapy for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever; discontinue therapy if ILD diagnosed

Potentially fatal GI perforations

Severe bullous, blistering, or exfoliating skin conditions

Ocular disorders include decreased tear production, abnormal eyelash growth, corneal perforation/ulceration, keratoconjunctivitis sicca, keratitis

Diarrhea

Smoking reduces erlotinib plasma concentration; advise patient to quit smoking

Monitor renal function and electrolytes, particularly in patients at risk of dehydration; withhold therapy for severe renal toxicity

Hepatotoxicity with or without hepatic impairment including hepatic failure and hepatorenal syndrome; monitor periodic liver testing; withhold or discontinue therapy for severe or worsening liver tests

Coadministration with CYP3A4 inhibitors/inducers

CYP1A2 inducers may decrease plasma concentration

Risk of myocardial infarction (MI)/ischemia is increased in patients with pancreatic cancer

Risk of cerebrovascular accident is increased in patients with pancreatic cancer

Risk of microangiopathic hemolytic anemia (MAHA) is increased in patients with pancreatic cancer

No evidence drug has any benefit after disease progression

Monitor if on warfarin or other coumarin-derived anticoagulants for changes in PT/INr

Avoid pregnancy; can cause fetal harm; advise females of reproductive potential of potential risk to fetus and to use highly effective contraception during therapy and for 1 month after the last dose

 

Pregnancy and lactation

 

Pregnancy

Based on animal data and its mechanism of action, erlotinib can cause fetal harm when administered to a pregnant woman

Advise females of reproductive potential to use effective contraception during treatment and for 1 month after the last dose

 

Lactation

No data exist on the presence of erlotinib in human milk, or the effects of erlotinib on the breastfed infant or on milk production

Because of the potential for serious adverse reactions in breastfed infants, including interstitial lung disease, hepatotoxicity, bullous and exfoliative skin disorders, microangiopathic hemolytic anemia, with thrombocytopenia, ocular disorders, and diarrhea

Advise a lactating woman not to breastfeed during treatment and for 2 weeks after the final dose

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Tarceva (erlotinib)

Mechanism of action

EGF receptor tyrosine kinase inhibitor; TKI inhibition possibly blocks angiogenesis and cellular proliferation

 

Pharmacokinetics

Absorption: 60%

Bioavailability: 60% (increased by food to almost 100%)

Peak Plasma Time: 4 hr

Half-life: 36 hr

Clearance: 24% higher in smokers

Protein Bound: 93%

Metabolism: primarily by CYP3A4; to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1

Excretion: Feces 83%; urine 8%

 

Pharmacogenomics

Erlotinib inhibits the tyrosine kinase (TK) domain of epidermal growth factors receptors (EGFRs) expressed on cell surface of lung cancers

Patients with EGFR exon 19 deletion or exon 21 L858R mutation have significantly better response to EGFR-TKIs

Genetic testing laboratories

• The following companies currently offer testing for mutations in the EGFR-TK domain
• Genzyme Genetics (https://www.genzymegenetics.com)
• LabCorp (https://www.labcorp.com)
• Response Genetics (https://www.responsegenetics.com)

 

Administration

Oral Administration

Take on empty stomach, 1 hr before or 2 hrs after meals