Gefitinib

Skin reactions occurred in nearly one-half of patients taking gefitinib. Bullous skin disorders, including toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme, and dermatitis bullous have been reported. Interrupt gefitinib treatment or discontinue for development of severe bullous, blistering, or exfoliating dermatologic conditions.

Diarrhea occurs in approximately one-third of patients; grade 3 or 4 diarrhea has been observed. Diarrhea symptoms should be managed as clinically indicated; avoid dehydration. Withhold gefitinib for severe or persistent (up to 14 days) diarrhea. Gastrointestinal perforation has occurred (rarely); discontinue permanently if gastrointestinal perforation develops. Nausea, vomiting, decreased appetite, and stomatitis have also been reported.

Increases in ALT, AST, and bilirubin, including grade 3 or higher toxicity have been observed. Fatal hepatotoxicity has occurred rarely. Monitor liver functions tests periodically. Withhold gefitinib in patients with worsening liver function; discontinue for severe hepatic impairment.

Ocular disorders, including keratitis, corneal erosion, abnormal eyelash growth, conjunctivitis, blepharitis, and dry eye have been reported; some events were grade 3. Recent corneal surgery and contact lens wearing may be risk factors for ocular toxicity. Advise patients to promptly report developing eye symptoms and promptly refer for ophthalmic evaluation if signs of keratitis (eg, acute or worsening of eye inflammation, lacrimation, blurred vision, pain, red eye, and/or light sensitivity). Interrupt gefitinib treatment or discontinue for severe or worsening ocular disorders.

Interstitial lung disease (ILD) or ILD-like reactions (eg, acute respiratory distress syndrome, lung infiltration, pneumonitis, or pulmonary fibrosis) have occurred (rarely) with gefitinib; some cases were grade 3 or higher and some were fatal. Withhold gefitinib and promptly assess any patient with worsening respiratory symptoms (dyspnea, cough, and fever); discontinue permanently if ILD is confirmed. Disease-related concerns:

Gefitinib exposure is increased in patients with mild, moderate, and severe hepatic impairment due to cirrhosis. However, in a study of patients with liver metastases, patients with metastases and moderate impairment had similar systemic exposure as patients with metastases and normal hepatic function. Monitor for adverse reactions if administering to patients with moderate or severe hepatic impairment. 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.

Elevated gastric pH may reduce gefitinib plasma concentrations; if possible, avoid concomitant use with proton pump inhibitors. If proton pump inhibitor therapy is necessary, administer gefitinib 12 hours before or 12 hours after the proton pump inhibitor dose. May administer gefitinib 6 hours before or 6 hours after H2-receptor antagonists or antacids. Special populations:

Systemic exposure of gefitinib may be increased in CYP2D6 poor metabolizers. No dosage adjustment is recommended, although patients should be monitored closely for adverse reactions. Other warnings/precautions:

Establish EGFR mutation status prior to treatment. Do not use in patients with EGFR mutation-negative tumors. Studies have demonstrated a subset of patients who are more likely to respond to gefitinib treatment. This subset includes patients of Asian origin, never-smokers, women, patients with bronchoalveolar adenocarcinoma, and patients with EGFR-mutated tumors. Deletion in exon 19 and mutation in exon 21 are the two most commonly found EGFR mutations; both mutations correlate with clinical response, resulting in increased response rates in patients with the mutation (Riely, 2006). Studies have compared gefitinib in treatment naïve patients to combination chemotherapy in the subsets of patients described above, resulting in a longer progression free survival in the gefitinib arm (Mok 2009). ASCO guidelines state that the first-line use of gefitinib may be recommended in stage IV disease with activating EGFR mutations (Masters 2015). In patients with a KRAS mutation, however, EGFR-TKI therapy is not recommended.