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: Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients receiving Alvoceva for treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of ILD (0.8%) was the same in both the placebo and Alvoceva groups. In a meta-analysis of NSCLC randomized controlled clinical trials (excluding phase I and single-arm phase II studies due to lack of control groups), the incidence of ILD-like events was 0.9% on erlotinib compared to 0.4% in patients in the control arms. In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2.5% in the Alvoceva plus gemcitabine group versus 0.4% in the placebo plus gemcitabine treated group. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome (ARDS), alveolitis, and lung infiltration. Symptoms started from a few days to several months after initiating Alvoceva therapy. Confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections were frequent. 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: Patients receiving Alvoceva are at increased risk of developing gastrointestinal perforation, which was observed uncommonly (including some cases with a fatal outcome). Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Alvoceva should be permanently discontinued in patients who develop gastrointestinal perforation (see Adverse Reactions).
Bullous and exfoliative skin disorders: Bullous, blistering and exfoliative skin conditions have been reported, including very rare cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal (see Adverse Reactions). Alvoceva treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions. Patients with bullous and exfoliative skin disorders should be tested for skin infection and treated according to local management guidelines.
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.