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Erlotinib

Pronunciation

(er LOE tye nib)

Index Terms

  • CP358774
  • Erlotinib Hydrochloride
  • OSI-774

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tarceva: 25 mg [contains fd&c yellow #6 (sunset yellow)]

Tarceva: 100 mg, 150 mg

Brand Names: U.S.

  • Tarceva

Pharmacologic Category

  • Antineoplastic Agent, Epidermal Growth Factor Receptor (EGFR) Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Reversibly inhibits overall epidermal growth factor receptor (HER1/EGFR) - tyrosine kinase activity. Intracellular phosphorylation is inhibited which prevents further downstream signaling, resulting in cell death. Erlotinib has higher binding affinity for EGFR exon 19 deletion or exon 21 L858R mutations than for the wild type receptor.

Absorption

Oral: 60% on an empty stomach; almost 100% on a full stomach

Distribution

232 L

Metabolism

Hepatic, via CYP3A4 (major), CYP1A1 (minor), CYP1A2 (minor), and CYP1C (minor)

Excretion

Primarily as metabolites: Feces (83%; 1% as unchanged drug); urine (8%%; <1% as unchanged drug)

Time to Peak

Plasma: 4 hours

Half-Life Elimination

36 hours

Protein Binding

~93% to albumin and alpha1-acid glycoprotein

Special Populations Note

Cigarette smoking: Smokers had a 24% higher rate of erlotinib clearance.

Use: Labeled Indications

Non-small cell lung cancer (NSCLC): First-line treatment of metastatic non-small cell lung cancer (NSCLC) in tumors with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an approved test; treatment of locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen; maintenance treatment of locally advanced or metastatic NSCLC which has not progressed after 4 cycles of first-line platinum-based chemotherapy

Limitations of use: Use in combination with platinum-based chemotherapy is not recommended. First-line treatment in patients with metastatic NSCLC with EGFR mutations other than exon 19 deletion or exon 21 (L858R) substitution has not been evaluated.

Pancreatic cancer (not an approved use in Canada): First-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer (in combination with gemcitabine)

Contraindications

There are no contraindications listed in the manufacturer’s U.S. labeling.

Canadian labeling: Hypersensitivity to erlotinib or any component of the formulation

Dosing: Adult

Non-small cell lung cancer (NSCLC), metastatic, first-line therapy in patients with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations: Oral: 150 mg once daily until disease progression or unacceptable toxicity (Rosell, 2012; Zhou, 2011).

NSCLC, refractory: Oral: 150 mg once daily until disease progression or unacceptable toxicity (Shepherd, 2005)

NSCLC, maintenance therapy: Oral: 150 mg once daily until disease progression or unacceptable toxicity (Capuzzo, 2010)

Pancreatic cancer: Oral: 100 mg once daily until disease progression or unacceptable toxicity (in combination with gemcitabine) (Moore, 2007)

Dosage adjustment for concomitant CYP3A4 inhibitors/inducers:

CYP3A4 inhibitors: Avoid concurrent use if possible; consider dose reductions for severe adverse reactions if erlotinib is administered concomitantly with strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, erythromycin, nefazodone, protease inhibitors, telithromycin, grapefruit, or grapefruit juice). Dose reduction (if required) should be done in decrements of 50 mg (after toxicity has resolved to baseline or ≤ grade 1).

Concomitant CYP3A4 and CYP1A2 inhibitor (eg, ciprofloxacin): Avoid concurrent use if possible; consider dose reductions in decrements of 50 mg if severe adverse reactions occur (after toxicity has resolved to baseline or ≤ grade 1).

CYP3A4 inducers: Alternatives to the enzyme-inducing agent should be utilized first. Concomitant administration with CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifamycins, and St John’s wort) may require increased erlotinib doses (increase as tolerated at 2-week intervals in 50 mg increments to a maximum of 450 mg); doses >150 mg daily should be considered with rifampin (the maximum erlotinib dose studied in combination with rifampin was 450 mg). Immediately reduce erlotinib dose to recommended starting dose when CYP3A4 inducer is discontinued.

Dosage adjustment for concomitant smoking: Increase dose at 2-week intervals in 50 mg increments to a maximum dose of 300 mg (with careful monitoring) in patients who continue to smoke; immediately reduce erlotinib dose to recommended starting dose upon smoking cessation.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Renal impairment at treatment initiation: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied), although <9% of a single dose is excreted in the urine.

Renal toxicity during treatment: Withhold treatment for grades 3/4 renal toxicity (consider discontinuing) and for risk of renal failure due to dehydration; may resume after euvolemia re-established (at previous dose). If treatment withheld due to toxicity and therapy is resumed, reinitiate with a 50 mg dose reduction after toxicity has resolved to baseline or ≤ grade 1.

Dosing: Hepatic Impairment

Hepatic impairment at treatment initiation:

U.S. labeling:

Total bilirubin > ULN or Child-Pugh classes A, B, and C: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor closely during treatment.

Total bilirubin >3 times ULN: Use extreme caution.

Canadian labeling:

Moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, a reduced dose should be considered.

Severe impairment (including total bilirubin >3 times ULN and/or transaminases >5 times ULN): Use is not recommended.

The following adjustments have also been studied: A reduced starting dose (75 mg once daily) has been recommended in patients with hepatic dysfunction (AST ≥3 times ULN or direct bilirubin 1-7 mg/dL), with individualized dosage escalation if tolerated (Miller, 2007); another study determined that pharmacokinetic and safety profiles were similar between patients with normal hepatic function and moderate hepatic impairment (O’Bryant, 2012).

Hepatotoxicity during treatment: U.S. labeling:

Patients with normal hepatic function at baseline: If total bilirubin >3 times ULN and/or transaminases >5 times ULN during use: Interrupt therapy (consider discontinuing); if treatment is resumed, reinitiate with a 50 mg dose reduction after bilirubin and transaminases return to baseline; discontinue treatment if there is no significant improvement or resolution within 3 weeks.

Patients with baseline hepatic impairment or biliary obstruction: If bilirubin doubles or transaminases triple over baseline during use: Interrupt therapy (consider discontinuing); if treatment is resumed, reinitiate with a 50 mg dose reduction after bilirubin and transaminases return to baseline; discontinue treatment if there is no significant improvement or resolution of hepatotoxicity within 3 weeks.

Dosing: Adjustment for Toxicity

Dermatologic toxicity:

Bullous, blistering, or exfoliative skin toxicity (severe): Discontinue treatment.

Severe rash (unresponsive to medical management): Withhold treatment; may reinitiate with a 50 mg dose reduction after toxicity has resolved to baseline or ≤ grade 1.

Gastrointestinal toxicity:

Diarrhea: Manage with loperamide; in severe diarrhea (unresponsive to loperamide) or dehydration due to diarrhea, withhold treatment; may reinitiate with a 50 mg dose reduction after toxicity has resolved to baseline or ≤ grade 1.

Gastrointestinal perforation: Discontinue treatment.

Ocular toxicities:

Acute or worsening ocular toxicities (eg, eye pain): Interrupt and consider discontinuing treatment. If therapy is resumed, reinitiate with a 50 mg dose reduction after toxicity has resolved to baseline or ≤ grade 1.

Corneal perforation or severe ulceration: Discontinue treatment.

Keratitis (grade 3 or 4 or grade 2 persisting >2 weeks): Withhold treatment; may reinitiate with a 50 mg dose reduction after toxicity has resolved to baseline or ≤ grade 1.

Pulmonary symptoms: Acute onset (or worsening) of pulmonary symptoms (eg, dyspnea, cough, fever): Interrupt treatment and evaluate for drug-induced interstitial lung disease; discontinue permanently with development of interstitial lung disease

Extemporaneously Prepared

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

A suspension for oral or feeding tube (silicone-based) administration may be prepared by dissolving tablets needed for dose in 100 mL water. To ensure full dose is received, rinse container with 40 mL water, administer residue and repeat rinse. Administer immediately after preparation; stability of solution is unknown (Data on file from Genentech [contact product manufacturer to obtain current information]).

Siu LL, Soulieres D, Chen EX, et al, “Phase I/II Trial of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group Study,” J Clin Oncol, 2007, 25(16):2178-83. [PubMed 17538162]17538162Soulieres D, Senzer NN, Vokes EE, et al, “Multicenter Phase II Study of Erlotinib, an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck,” J Clin Oncol, 2004, 22(1):77-85. [PubMed 14701768]14701768

Administration

The manufacturer recommends administration on an empty stomach (at least 1 hour before or 2 hours after the ingestion of food). Avoid concomitant use with proton pump inhibitors. If taken with an H2-receptor antagonist (eg, ranitidine), administer erlotinib 10 hours after the H2-receptor antagonist dose and at least 2 hours prior to the next H2- receptor dose. If an antacid is necessary, separate dosing by several hours.

For patients unable to swallow whole, tablets may be dissolved in 100 mL water and administered orally or via feeding tube (silicone-based); to ensure full dose is received, rinse container with 40 mL water, administer residue and repeat rinse (data on file, Genentech [contact product manufacturer to obtain current information]; Siu, 2007; Soulieres, 2004).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

Take this medicine on an empty stomach, 1 hour before or 2 hours after a meal. Avoid grapefruit juice.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Antacids: May decrease the serum concentration of Erlotinib. Management: Separate the administration of erlotinib and any antacid by several hours in order to minimize the risk of a significant interaction. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50mg decrements). Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Erlotinib. Management: Avoid combination if possible. If combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

FluvoxaMINE: May increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

H2-Antagonists: May decrease the serum concentration of Erlotinib. Management: Avoid H2-antagonists in patients receiving erlotinib when possible. If concomitant treatment cannot be avoided, erlotinib should be dosed once daily, 10 hours after and at least 2 hours before H2-antagonist dosing. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Proton Pump Inhibitors: May decrease the serum concentration of Erlotinib. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Erlotinib. Management: Avoid combination if possible. If combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Warfarin: Erlotinib may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

Adverse reactions reported with monotherapy:

>10%:

Cardiovascular: Chest pain (≤18%)

Central nervous system: Fatigue (9% to 52%)

Dermatologic: Skin rash (49% to 85%; grade 3: 5% to 13%; grade 4: <1%; median onset: 8 days), xeroderma (4% to 21%), pruritus (7% to 16%), paronychia (4% to 16%), alopecia (14% to 15%), acne vulgaris (6% to 12%)

Gastrointestinal: Diarrhea (20% to 62%; grade 3: 2% to 6%; grade 4: <1%; median onset: 12 days), anorexia (9% to 52%), nausea (23% to 33%), decreased appetite (≤28%), vomiting (13% to 23%), mucositis (≤18%), stomatitis (11% to 17%), abdominal pain (3% to 11%), constipation (≤8%)

Genitourinary: Urinary tract infection (≤4%)

Hematologic & oncologic: Anemia (≤11%; grade 4: 1%)

Infection: Increased susceptibility to infection (4% to 24%)

Miscellaneous: Fever (≤11%)

Neuromuscular & skeletal: Weakness (≤53%), back pain (19%), arthralgia (≤13%), musculoskeletal pain (11%)

Ophthalmic: Conjunctivitis (12% to 18%), keratoconjunctivitis sicca (12%)

Respiratory: Cough (33% to 48%), dyspnea (41% to 45%; grades 3/4: 8% to 28%)

1% to 10%:

Cardiovascular: Peripheral edema (≤5%)

Central nervous system: Pain (≤9%), headache (≤7%), anxiety (≤5%), dizziness (≤4%), insomnia (≤4%), neurotoxicity (≤4%), paresthesia (≤4%), voice disorder (≤4%)

Dermatologic: Folliculitis (≤8%), nail disease (≤7%), exfoliative dermatitis (5%), hypertrichosis (5%), skin fissure (5%), acneiform eruption (4% to 5%), erythema (≤5%), dermatitis (4%), erythematous rash (≤4%), palmar-plantar erythrodysesthesia (≤4%), bullous dermatitis

Endocrine & metabolic: Weight loss (4% to 5%)

Gastrointestinal: Dyspepsia (≤5%), xerostomia (≤3%), taste disorder (≤1%)

Hematologic & oncologic: Lymphocytopenia (≤4%; grade 3: 1%), leukopenia (≤3%), thrombocytopenia (≤1%)

Hepatic: Hyperbilirubinemia (7%; grade 3: ≤1%), increased serum ALT (grade 2: 2% to 4%; grade 3: 1% to 3%), increased gamma-glutamyl transferase (≤4%), hepatic failure (≤1%)

Neuromuscular & skeletal: Muscle spasm (≤4%), musculoskeletal chest pain (≤4%), ostealgia (≤4%)

Otic: Tinnitus (≤1%)

Renal: Increased serum creatinine (≤1%), renal failure (≤1%),

Respiratory: Nasopharyngitis (≤7%), epistaxis (≤4%), pulmonary embolism (≤4%), respiratory tract infection (≤4%), pneumonitis (3%), pulmonary fibrosis (3%)

<1%: Interstitial pulmonary disease

Adverse reactions reported with combination (erlotinib plus gemcitabine) therapy:

>10%:

Cardiovascular: Edema (37%), thrombosis (grades 3/4: 11%)

Central nervous system: Fatigue (73% to 79%), depression (19%), dizziness (15%), headache (15%), anxiety (13%)

Dermatologic: Skin rash (70%), alopecia (14%)

Gastrointestinal: Nausea (60%), anorexia (52%), diarrhea (48%), abdominal pain (46%), vomiting (42%), weight loss (39%), stomatitis (22%), dyspepsia (17%), flatulence (13%)

Hepatic: Increased serum ALT (grade 2: 31%, grade 3: 13%, grade 4: <1%), increased serum AST (grade 2: 24%, grade 3: 10%, grade 4 <1%), hyperbilirubinemia (grade 2: 17%, grade 3: 10%, grade 4: <1%)

Infection: Increased susceptibility to infection (39%)

Miscellaneous: Fever (36%)

Neuromuscular & skeletal: Ostealgia (25%), myalgia (21%), neuropathy (13%), rigors (12%)

Respiratory: Dyspnea (24%), cough (16%)

1% to 10%:

Cardiovascular: Cardiac arrhythmia (<5%), syncope (<5%), deep vein thrombosis (4%), cerebrovascular accident (3%; including cerebral hemorrhage), myocardial infarction (2%)

Gastrointestinal: Intestinal obstruction (<5%), pancreatitis (<5%)

Hematologic & oncologic: Hemolytic anemia (<5%), microangiopathic hemolytic anemia with thrombocytopenia (1%)

Renal: Renal insufficiency (<5%), renal failure (1%)

Respiratory: Interstitial pulmonary disease (<3%)

<1%: Bullous dermatitis, exfoliative dermatitis, hepatic failure

Mono- or combination therapy: <1% (Limited to important or life-threatening): Acute peptic ulcer with hemorrhage, bronchiolitis, corneal perforation, corneal ulcer, episcleritis, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, hearing loss, hematemesis, hematochezia, hepatorenal syndrome, hepatotoxicity, hirsutism, hyperpigmentation, hypokalemia, keratitis, melena, myopathy (in combination with statin therapy), peptic ulcer, rhabdomyolysis (in combination with statin therapy), skin photosensitivity, skin rash (acneiform; sparing prior radiation field), Stevens-Johnson syndrome, toxic epidermal necrolysis, tympanic membrane perforation

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular events: Cerebrovascular accidents, MI, and myocardial ischemia have been reported.

• Dermatologic toxicity: Bullous, blistering, or exfoliating skin conditions, some suggestive of Stevens-Johnson or toxic epidermal necrolysis (TEN), have been reported (some fatal). An acne-like rash commonly appears on the face, back, and upper chest. Generalized or severe acneiform, erythematous or maculopapular rash may occur. Skin rash may correlate with treatment response and prolonged survival (Saif, 2008); management of skin rashes that are not serious should include alcohol-free lotions, topical antibiotics, or topical corticosteroids, or if necessary, oral antibiotics and systemic corticosteroids; avoid sunlight. Reduce dose or temporarily interrupt treatment for severe skin reactions; discontinue treatment for bullous, blistering, or exfoliative skin toxicity.

• Gastrointestinal (GI) perforation: GI perforation (including fatalities) has been reported with use; risk for perforation is increased with concurrent anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based-therapy, and patients with history of peptic ulcers or diverticular disease. Permanently discontinue in patients who develop perforation.

• Hematologic effects: Microangiopathic hemolytic anemia (MAHA) with thrombocytopenia has been reported (rarely) with erlotinib in combination with gemcitabine.

• Hemorrhage: Elevated INR and bleeding events (including fatal hemorrhage) have been reported when erlotinib was administered concomitantly with warfarin; monitor prothrombin time and INR closely.

• Hepatotoxicity: Hepatic failure and hepatorenal syndrome have been reported (some fatal), particularly in patients with baseline hepatic impairment (although have also been observed in patients with normal hepatic function). Monitor liver function (transaminases, bilirubin, and alkaline phosphatase); patients with any hepatic impairment (total bilirubin >ULN; Child-Pugh class A, B, or C) should be closely monitored, including those with hepatic disease due to tumor burden. Increased monitoring of liver function is required in patients with preexisting hepatic impairment or biliary obstruction. Dosage reduction, interruption, or discontinuation may be recommended for changes in hepatic function. Use with extreme caution in patients with total bilirubin >3 times ULN. Interrupt therapy if total bilirubin is >3 times ULN or transaminases are >5 times ULN in patients without preexisting hepatic impairment. In patients with baseline hepatic dysfunction or biliary obstruction, interrupt therapy if bilirubin doubles or transaminases triple from baseline values.

• Ocular toxicity: Corneal perforation and ulceration have been reported with use; decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca, or keratitis have also been reported and are known risk factors for corneal ulceration/perforation. Interrupt or discontinue treatment in patients presenting with eye pain or other acute or worsening ocular symptoms. Consider a baseline ophthalmologic exam and reassess for ocular toxicities at 4 to 8 weeks after treatment initiation (Renouf, 2012).

• Pulmonary toxicity: Rare, sometimes fatal, interstitial lung disease (ILD) has occurred; symptoms include acute respiratory distress syndrome, interstitial pneumonia, obliterative bronchiolitis, pneumonitis (including radiation and hypersensitivity), pulmonary fibrosis, and pulmonary infiltrates. The onset of symptoms has been within 5 days to more than 9 months after treatment initiation (median: 39 days). Interrupt treatment for unexplained new or worsening pulmonary symptoms (dyspnea, cough, and fever); permanently discontinue for confirmed ILD.

• Renal impairment: Acute renal failure (some fatal), renal insufficiency, and hepatorenal syndrome have been reported, either secondary to hepatic impairment at baseline or due to severe dehydration; use with caution in patients with or at risk for renal impairment. Monitor closely for dehydration; monitor renal function and electrolytes in patients at risk for dehydration. If severe renal impairment develops, interrupt therapy until toxicity resolves.

Disease-related concerns:

• NSCLC genomics: EGFR mutations, specifically exon 19 deletions and exon 21 mutation (L858R), are associated with better response to erlotinib in patients with NSCLC (Riely, 2006). Erlotinib treatment is not recommended in patients with NSCLC with K-ras mutations; they are not likely to benefit from erlotinib treatment (Eberhard, 2005; Miller, 2008). The cobas EGFR mutation test has been approved to detect EGFR mutation for first-line NSCLC treatment.

Concurrent drug therapy issues:

• Drugs affecting gastric pH: Avoid concomitant use with proton pump inhibitors. If taken with an H2-receptor antagonist (eg, ranitidine), administer erlotinib 10 hours after the H2-receptor antagonist dose and at least 2 hours prior to the next H2-receptor dose. If an antacid is necessary, separate dosing by several hours.

• 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:

• Smokers: Erlotinib levels may be lower in patients who smoke; advise patients to stop smoking. Smokers treated with 300 mg/day exhibited steady-state erlotinib levels comparable to former- and never-smokers receiving 150 mg/day (Hughes, 2009).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate use: Concurrent erlotinib plus platinum-based chemotherapy is not recommended for treatment of locally-advanced or metastatic NSCLC due to a lack of clinical benefit.

• Lactose intolerance: Product may contain lactose; avoid use in patients with Lapp lactase deficiency, glucose-galactose malabsorption, or glucose intolerance.

Monitoring Parameters

Periodic liver function tests (transaminases, bilirubin, and alkaline phosphatase); monitor more frequently with worsening liver function; periodic renal function tests and serum electrolytes (in patients at risk for dehydration); hydration status; signs/symptoms of pulmonary toxicity; prothrombin time and INR (in patients on concomitant warfarin therapy); consider a baseline ophthalmologic exam and reassess for ocular toxicities at 4 to 8 weeks after treatment initiation (Renouf, 2012); EGFR mutation status in patients with NSCLC adenocarcinoma (Keedy, 2011); the cobas EGFR mutation test has been approved to detect EGFR mutation for first-line NSCLC treatment

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, may cause fetal harm if administered in pregnancy. Females of reproductive potential should be advised to avoid pregnancy; highly effective contraception is recommended during treatment and for at least 2 weeks after treatment has been completed.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience acne vulgaris, lack of appetite, stomatitis, headache, back pain, arthralgia, myalgia, hair or nail changes, or xeroderma. Have patient report immediately to prescriber signs of infection, signs of hepatic impairment, signs of renal impairment, signs of pulmonary disorder, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, angina, severe nausea, considerable diarrhea, ecchymosis, hemorrhaging, intolerable asthenia, vision changes, ophthalmalgia, significant eye irritation, excessive weight loss, depression, severe dyspepsia, hematemesis, melena, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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