Erlotinib

Cerebrovascular accidents, MI, and myocardial ischemia have been reported (some fatal).

Bullous, blistering, and/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.

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

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

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

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 and more frequently 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 necessary 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.

Corneal perforation and ulceration have been reported; 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).

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.

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:

Some factors which correlate positively with response to EGFR-tyrosine kinase inhibitor (TKI) therapy in NSCLC include patients who have never smoked, EGFR mutation, and patients of Asian origin. 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). K-ras mutations correlated with poorer outcome with EGFR-TKI therapy in patients with NSCLC (Jackman 2009; Masarelli 2007; Shepherd 2005). The cobas EGFR mutation test has been approved to detect EGFR mutation for NSCLC treatment. Concurrent drug therapy issues:

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.

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. Special populations:

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). Other warnings/precautions:

Concurrent erlotinib plus platinum-based chemotherapy is not recommended for treatment of locally-advanced or metastatic NSCLC due to a lack of clinical benefit. Treatment in patients with metastatic NSCLC with EGFR mutations other than exon 19 deletion or exon 21 (L858R) substitution has not been evaluated. Select patients for metastatic NSCLC treatment based on EGFR exon 19 deletions and exon 21 mutation (L858R) in tumor or plasma specimens; if these mutations are not detected in plasma specimen, tumor tissue (if available) may be tested.

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