Assessment of EGFR mutation status: When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.
Smokers: Current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as compared to non-smokers are reduced. The degree of reduction is likely to be clinically significant (see Interactions).
Interstitial Lung Disease: In the principal efficacy study for non-small cell lung cancer, the reported incidence of interstitial lung disease-like events (0.8%) was similar among patients receiving erlotinib and those receiving placebo. In the principal efficacy study for pancreatic cancer, interstitial lung disease-like events occurred in 2.5% of patients receiving erlotinib and gemcitabine versus 0.4% of those receiving placebo and gemcitabine.
Reported diagnoses in patients suspected of having interstitial lung disease-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, and lung infiltration.
Among patients receiving erlotinib for non-small cell lung cancer, most of these cases were associated with confounding or contributing factors, including concomitant for, prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections.
Interruption or discontinuance of erlotinib therapy may be required in patients experiencing pulmonary toxicity.
A higher incidence of ILD (approximately 5% with a mortality rate of 1.5%) is seen among patients in studies conducted in Japan.
In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, ALVOCEVA therapy should be interrupted pending diagnostic evaluation. Patients treated concurrently with erlotinib and gemcitabine should be monitored carefully for the possibility to develop ILD-like toxicity. If ILD is diagnosed, ALVOCEVA should be discontinued and appropriate treatment initiated as necessary (see Adverse Reactions).
Diarrhoea, dehydration, electrolyte imbalance and renal failure: Diarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50% of patients on ALVOCEVA and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps. Dose reductions by 25 mg steps have not been investigated. In the event of severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, ALVOCEVA therapy should be interrupted and appropriate measures should be taken to treat the dehydration (see Adverse Reactions). There have been rare reports of hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (especially concomitant chemotherapy and other medications, symptoms or diseases or other predisposing conditions including advanced age), ALVOCEVA therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration.
Hepatitis, hepatic failure: Rare cases of hepatic failure (including fatalities) have been reported during use of ALVOCEVA. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function testing should be considered. ALVOCEVA dosing should be interrupted if changes in liver function are severe (see Adverse Reactions). ALVOCEVA is not recommended for use in patients with severe hepatic dysfunction.
Gastrointestinal perforation: GI perforation, sometimes fatal, has been reported in patients receiving erlotinib. Patients with a history of peptic ulcer disease or diverticulitis and those who are receiving concomitant therapy with anti angicogenesis drugs, corticosteroids, nonsteroidal anti-inflammatory agents (NSAIAs), and/or taxane-based chemotherapy are at increased risk for perforation while receiving erlotinib therapy. If perforation occurs, erlotinib therapy should be permanently discontinued. (see Adverse Reactions).
Bullous and exfoliative skin disorders: Bullous, blistering and exfoliative skin reactions, including cases suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis, have been reported in patients receiving erlotinib therapy; some cases have been fatal (see Adverse Reactions). If severe bullous, blistering or exfoliative disorders occur, erlotinib therapy should be interrupted or discontinued.
Ocular disorders: Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with ALVOCEVA should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. ALVOCEVA should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration. Very rare cases of corneal perforation or ulceration have been reported during use of ALVOCEVA (see Adverse Reactions).
Interactions with other medicinal products: Potent inducers of CYP3A4 may reduce the efficacy of erlotinib whereas potent inhibitors of CYP3A4 may lead to increased toxicity. Concomitant treatment with these types of agents should be avoided (see Interactions).
Other forms of interactions: Erlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter the pH of the upper Gastro-Intestinal (GI) tract, like proton pump inhibitors, H2 antagonists and antacids, may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of ALVOCEVA when co-administered with such agents is not likely to compensate for the loss of exposure. Combination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. Therefore, concomitant administration of these combinations should be avoided (see Interactions). If the use of antacids is considered necessary during treatment with ALVOCEVA, they should be taken at least 4 hours before or 2 hours after the daily dose of ALVOCEVA.
The tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed; however erlotinib is not associated with impairment of mental ability.