Monotherapy of adult patients previously untreated with epidermal growth factor receptor (TKI EGFR) receptor tyrosine kinase inhibitors with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation (mutations).
Composition:
1 tabl powl. contains 20 mg, 30 mg or 40 mg afatinib (as dimaleate). The preparation contains lactose.
Action:
An anti-cancer drug. Afatinib is a potent and selective, irreversible inhibitor of the ErbB family of receptors. It binds covalently and irreversibly blocks signaling from all homo- and heterodimers formed by the EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 receptors of the ErbB family. After oral administration of Cmax occurs after approx. 2-5 h. Systemic exposure to afatinib taken with a fat-rich meal decreases by 50% (Cmax) and 39% (AUC) compared with fasting. In conditionsin vitro the afatinib binding rate to human plasma proteins is approximately 95%. Afatinib binds to proteins both non-covalently (in a traditional way) and covalently. Metabolic reactions catalyzed by enzymes do not play a significant role for afatinibin vivo. Most of the circulating aflatinib metabolites are adducts covalently linked to proteins. In humans, afatinib is mainly excreted in the faeces (85.4% of the dose); 4.3% of the dose is excreted in the urine. The parent compound is 88% of the detected dose. T0,5 afatinib is approximately 37 hrs. Plasma concentrations of afatinib occur within 8 days of repeated afatinib dosing, resulting in 2.77-fold accumulation in the AUC range and 2.11-fold accumulation in the C rangemax.
Contraindications:
Hypersensitivity to afatinib or to any of the excipients.
Precautions:
When assessing the status of an EGFR mutation in a patient, it is important to select a correctly validated and reliable methodology to avoid false negative or false positive results. Diarrhea, including severe diarrhea, has been reported during treatment. Diarrhea usually occurred in the first 2 weeks of treatment. Grade 3 diarrhea occurred usually in the first 6 weeks of treatment. Active treatment of diarrhea, including adequate hydration combined with antidiarrheal medications, especially in the first 6 weeks of treatment plays an important role and should be initiated after the onset of the first symptoms of diarrhea. Antidiarrheal medications (eg loperamide) should be used and, if necessary, the maximum dose allowed. Antidiarrhoeal medications should be readily available to patients so that they can be used after the first symptoms of diarrhea and continue treatment for at least 12 hours after achieving normal peristalsis and resolution of diarrhea. Patients who have experienced severe diarrhea may need to stop treatment and reduce the dose or discontinue treatment altogether. Dehydration patients may require intravenous administration of electrolytes and fluids. There have been reports of rash / acne in patients treated with the preparation. The rash is usually a mild to moderate erythematous and acne-like rash that may or may be present in areas exposed to the sun. Patients who are exposed to the sun are advised to use protective clothing and protective preparations with sunscreen. Early treatment of skin reactions (moisturizing preparations, antibiotics) may facilitate long-term use of the preparation. In patients with severe skin reactions, it may also be necessary to temporarily discontinue therapy, reduce the dose, and provide additional treatment and referral to a specialist for the treatment of dermatological symptoms. Discontinue or stop treatment altogether if the patient develops severe blistering or exfoliative lesions. Higher exposure to afatinib has been observed in women, patients with lower body weight and with impaired renal function. This may result in a higher risk of side effects, in particular diarrhea, rash / acne and inflammation of the mouth.In patients with the above-mentioned risk factors, closer monitoring is recommended. There have been reports of cases of interstitial lung disease or adverse reactions with a similar disease picture (eg infiltration in the lungs, pneumonia, acute respiratory distress syndrome, allergic alveolitis), in this case fatal, in patients receiving the preparation for treatment of NSCLC. To exclude interstitial lung disease, all patients with pulmonary signs (dyspnea, cough, fever) with acute onset and / or unexplained severity should be carefully evaluated. The treatment should be discontinued until the assessment of these symptoms has been completed. If an interstitial lung disease is diagnosed, treatment should be discontinued and appropriate treatment initiated as necessary. Hepatic insufficiency, sometimes fatal, has been reported during treatment with the preparation. The risk factors in these patients included pre-existing liver disease and / or co-morbidities associated with the progression of the basic neoplastic disease. Periodic liver function tests are recommended in patients with pre-existing liver disease. Discontinuation of treatment may be necessary in people with worsening liver function. Treatment should be permanently discontinued in patients who develop severe liver problems. In the event of symptoms such as: acute or worsening eye inflammation, tearing, photosensitivity, blurred vision, eye pain and / or redness of the eye, immediately report to an ophthalmologist. If confirmation of ulcerative keratitis is confirmed, treatment with the preparation should be temporarily stopped or discontinued. If you are diagnosed with keratitis, all the benefits and risks of continuing treatment should be considered. Caution should be exercised when using the product in patients with a history of keratitis, ulcerative keratitis or a severe form of dry eye. The use of contact lenses is also a risk factor for corneal inflammation and ulceration. A relationship was found between left ventricular dysfunction and HER2 inhibition. Available data from clinical trials do not indicate any adverse effect of afatinib on myocardial contractility. However, no studies have been conducted with afatinib in patients with abnormal left ventricular ejection fraction (LVEF) or with serious history of cardiac disease. In patients with cardiac risk factors and those with underlying diseases that may affect LVEF, consideration of cardiac function should be considered, including evaluation of the level of LVEF before and after the initiation of afatinib treatment. Patients who develop cardiac symptoms during treatment should consider cardiac function, including LVEF. In patients with ejection fraction below the lower limit of normal, cardiac consultation and temporary interruption or termination of treatment with the preparation should be considered. Co-administration with potent P-gp inducers may reduce exposure to afatinib. It is not recommended for use in children and adolescents. The product contains lactose - should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Pregnancy and lactation:
For safety reasons, women of childbearing age should be advised to avoid becoming pregnant while using the product. During treatment and for at least 1 month after the last dose, appropriate methods of contraception should be used. Considering the mechanism of action, all drugs targeting EGFR are potentially harmful to the fetus. There are no or limited data on the use of the preparation in pregnant women. The risk to people is unknown. If the preparation is used during pregnancy or if the patient becomes pregnant during or after treatment, it should be informed of the potential risk to the fetus. It is likely that afatinib passes into human milk. Breastfeeding mothers receiving the preparation should be advised against. The available non-clinical toxicological data showed the effect of higher doses on the reproductive system, therefore the negative effects of the preparation on human fertility can not be excluded.
Orally. Treatment should be started and supervised by a doctor who has experience in the field of anticancer treatment. The EGFR mutation status should be confirmed before starting the treatment with the preparation. Adults: the recommended dose is 40 mg once a day. The drug should be taken on an empty stomach. Do not eat at least 3 hours before and 1 hour after taking the product. Treatment should be continued until the disease progresses or is not tolerated by the patient.Increasing the dose. A dose increase up to a maximum of 50 mg / day may be considered for patients who tolerate a 40 mg / day dose (i.e. no diarrhea, skin rash, stomatitis and other grade 1 adverse events> 1 according to CTCAE) during the first three weeks. dose should be increased in patients who have previously been reduced. The maximum daily dose is 50 mg.Dose adjustment for side effects. An effective way of dealing with symptomatic side effects (eg severe / persistent diarrhea or cutaneous side effects) may be a reduction in the dose or discontinuation of treatment with the preparation. CTCAE grade 1 or 2 adverse reactions - no interruption in treatment; no dose modification; in the event of diarrhea, immediately take antidiarrheal medicine (eg loperamide), and in the case of persistent diarrhea, continue to take it until it disappears. Grade 2 adverse reactions prolonged (diarrhea lasting> 48 h and / or rash> 7 days) or not tolerated or grade ≥3. - treatment should be stopped until grade 0/1 is reached; if diarrhea occurs, immediately take antidiarrheal medications (eg loperamide), and in case of persistent diarrhea, continue taking it until it disappears; resumption of therapy at a dose reduced by 10 mg (if the patient can not tolerate a 20 mg / day dose, the end of treatment with the preparation should be considered). In the case of acute or worsening respiratory symptoms, treatment should be discontinued until a medical assessment is made. If an interstitial lung disease is diagnosed, treatment should be discontinued and appropriate treatment initiated as necessary. If you miss a dose, take it as soon as possible on the same day. However, if the Next dose should be taken within 8 hours, do not take the missed dose. If P-gp inhibitors are required, they should be given alternately, ie the dose of the P-gp inhibitor should be taken as much as possible from the time the dose is given. Ideally, 6h (in the case of P-gp inhibitors administered twice daily) or 12 h (in the case of P-gp inhibitors administered once a day) after administration. No adjustment of the initial dose is required in patients with mild or moderate renal impairment. It is not recommended for patients with severe renal impairment (creatinine clearance <30 ml / min). No adjustment of the initial dose is required in patients with mild or moderate hepatic impairment (Child-Pugh A and B). Use in patients with severe hepatic impairment (Child-Pugh C) is not recommended.Method of administration. The tablets should be swallowed whole with water. If swallowing the whole tablet is not possible, it can be dissolved in 100 ml of non-carbonated water. Do not use any other liquids.The tablet should be placed in a glass of water without breaking it first, stirring occasionally for a maximum of 15 min, until it disintegrates into very small particles. The suspension should be drunk immediately. The glass should be rinsed with approximately 100 ml of water, which should also be drunk. The suspension may also be administered by gastric tube.
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