Presentation and Status in Health Basket
Film Coated Tablets
28 X 20 mg
Film Coated Tablets
28 X 30 mg
Film Coated Tablets
28 X 40 mg
Film Coated Tablets
28 X 50 mg
Treatment with Afatinib should be initiated and supervised by a physician experienced in the use of anticancer therapies.
EGFR mutation status should be established prior to initiation of AFATINIB therapy.
The recommended dose is 40 mg once daily. This medicinal product should be taken without food. Food should not be consumed for at least 3 hours before and at least 1 hour after taking this medicinal product. Afatinib treatment should be continued until disease progression or until no longer tolerated by the patient.
Dose escalation: A dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a 40 mg/day dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE Grade > 1) in the first 3 weeks. The dose should not be escalated in any patients with a prior dose reduction. The maximum daily dose is 50 mg.
Dose adjustment for adverse reactions: Symptomatic adverse reactions (e.g. severe/persistent diarrhoea or skin related adverse reactions) may be successfully managed by treatment interruption and dose reductions or treatment discontinuation of Afatinib as outlined next:
Dose adjustment information for adverse reactions:
Grade 1 or grade 2 CTCAEa adverse reaction – no interruption or dose adjustment.
Grade 2 (prolongedc or intolerable) or grade ≥ 3 – interrupt until grade 0/1b. Resume with dose reduction by 10 mg incrementsd.
a– NCI Common Terminology Criteria for Adverse Events.
b -In case of diarrhoea, anti-diarrhoeal medicinal products (e.g. loperamide) should be taken immediately and continued for persistent diarrhoea until loose bowel movements cease.
c -> 48 hours of diarrhoea and/or > 7 days of rash.
d– If patient cannot tolerate 20 mg/day, permanent discontinuation of Afatinib should be considered. Interstitial Lung Disease (ILD) should be considered if a patient develops acute or worsening of respiratory symptoms in which case treatment should be interrupted pending evaluation. If ILD is diagnosed, Afatinib should be discontinued and appropriate treatment initiated as necessary.
Missed dose: If a dose is missed, it should be taken within the same day as soon as the patient remembers. However, if the next scheduled dose is due within 8 hours then the missed dose must be skipped.
Use of P-glycoprotein (P-gp) inhibitors: If P-gp inhibitors need to be taken, they should be administered using staggered dosing, i.e. the P-gp inhibitor dose should be taken as far apart in time as possible from the Afatinib dose. This means preferably 6 hours (for P-gp inhibitors dosed twice daily) or 12 hours (for P-gp inhibitors dosed once daily) apart from Afatinib.
Patients with renal impairment: The safety, pharmacokinetics and efficacy of this medicinal product have not been studied in a dedicated trial in patients with renal impairment. Adjustments to the starting dose are not necessary in patients with mild or moderate renal impairment. Treatment in patients with severely impaired renal function (< 30 mL/min creatinine clearance) is not recommended.
Patients with hepatic impairment: Exposure to afatinib is not significantly changed in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Adjustments to the starting dose are not necessary in patients with mild or moderate hepatic impairment. This medicinal product has not been studied in patients with severe (Child Pugh C) hepatic impairment. Treatment in this population is not recommended.
Paediatric population: There is no relevant use of Afatinib in the paediatric population in the indication of NSCLC. Therefore, treatment of children or adolescents with this medicinal product is not recommended.
Method of administration: This medicinal product is for oral use. The tablets should be swallowed whole with water. If swallowing of whole tablets is not possible, these can be dispersed in approximately 100 ml of noncarbonated drinking water. No other liquids should be used. The tablet should be dropped into the water without crushing it, and stirred occasionally for up to 15 min until it is broken up into very small particles. The dispersion should be consumed immediately. The glass should be rinsed with approximately 100 ml of water which should also be consumed. The dispersion can also be administered through a gastric tube.
Afatinib as monotherapy is indicated for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI-naïve adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation;
locally advanced or metastatic NSCLC of squamous histology progressing on or after platinumbased chemotherapy.
Hypersensitivity to afatinib or to any of the excipients.
If you are pregnant or breastfeeding.
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.
Diarrhoea: Diarrhoea, including severe diarrhoea, has been reported during treatment with AFATINIB. Diarrhoea may result in dehydration with or without renal impairment, which in rare cases has resulted in fatal outcomes. Diarrhoea usually occurred within the first 2 weeks of treatment. Grade 3 diarrhoea most frequently occurred within the first 6 weeks of treatment. Proactive management of diarrhoea including adequate hydration combined with anti-diarrhoeal medicinal products especially within the first 6 weeks of the treatment is important and should start at first signs of diarrhoea. Antidiarrhoeal medicinal products (e.g. loperamide) should be used and if necessary their dose should be escalated to the highest recommended approved dose. Anti-diarrhoeal medicinal products should be readily available to the patients so that treatment can be initiated at first signs of diarrhoea and continued until loose bowel movements cease for 12 hours. Patients with severe diarrhoea may require interruption and dose reduction or discontinuation of therapy with Afatinib. Patients who become dehydrated may require administration of intravenous electrolytes and fluids.
Skin related adverse events: Rash/acne has been reported in patients treated with this medicinal product. In general, rash manifests as a mild or moderate erythematous and acneiform rash, which may occur or worsen in areas exposed to sun. For patients who are exposed to sun, protective clothing, and use of sun screen is advisable. Early intervention (such as emollients, antibiotics) of dermatologic reactions can facilitate continuous Afatinib treatment. Patients with severe skin reactions may also require temporary interruption of therapy, dose reduction, additional therapeutic intervention, and referral to a specialist with expertise in managing these dermatologic effects. Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome. Treatment with this medicinal product should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.
Female gender, lower body weight, and underlying renal impairment: Higher exposure to Afatinib has been observed in female patients, patients with lower body weight and those with underlying renal impairment. This could result in a higher risk of developing adverse reactions in particular diarrhoea, rash/acne and stomatitis. Closer monitoring is recommended in patients with these risk factors.
Interstitial Lung Disease (ILD): There have been reports of ILD or ILD-like adverse reactions (such as lung infiltration, pneumonitis, acute respiratory distress syndrome, allergic alveolitis), including fatalities, in patients receiving Afatinib for treatment of NSCLC. ILD-like adverse reactions were reported in 0.7% of more than 3,800 patients treated. CTCAE Grade ≥ 3 ILD-like adverse reactions were reported in 0.5% of patients. Patients with a history of ILD have not been studied. Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Treatment with this medicinal product should be interrupted pending investigation of these symptoms. If ILD is diagnosed, Afatinib should be permanently discontinued and appropriate treatment initiated as necessary.
Severe hepatic impairment: Hepatic failure, including fatalities, has been reported during treatment with this medicinal product in less than 1% of patients. In these patients, confounding factors have included pre-existing liver disease and/or comorbidities associated with progression of underlying malignancy. Periodic liver function testing is recommended in patients with pre-existing liver disease. Grade 3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations were observed in 2.4% of patients with normal baseline liver tests treated with 40 mg/day, and were about 3.5 fold higher in patients with abnormal baseline liver tests. Dose interruption may become necessary in patients who experience worsening of liver function. In patients who develop severe hepatic impairment while taking Afatinib, treatment should be discontinued.
Keratitis: Symptoms 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 should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. This medicinal product 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.
Left ventricular function: Left ventricular dysfunction has been associated with HER2 inhibition. Based on the available clinical trial data, there is no suggestion that this medicinal product causes an adverse reaction on cardiac contractility. However, this medicinal product has not been studied in patients with abnormal left ventricular ejection fraction (LVEF) or those with significant cardiac history. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be considered. In patients with an ejection fraction below the institution’s lower limit of normal, cardiac consultation as well as treatment interruption or discontinuation should be considered.
P-glycoprotein (P-gp) interactions: Concomitant treatment with strong inducers of P-gp may decrease exposure to afatinib.
Lactose: This medicinal product contains lactose. Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
See prescribing information for full details.
Very common: Paronychia, Decreased appetite, Epistaxis, Diarrhoea,
Stomatitis, Nausea, Vomiting, Rash, Dermatitis acneiform, Pruritus, Dry skin.
Common: Cystitis, Dehydration, Hypokalaemia, Dysgeusia, Conjunctivitis,
Dry eye, Rhinorrhoea, Dyspepsia, Cheilitis, Alanine aminotransferase increased,
Aspartate aminotransferase increased, Palmar-plantar erythrodysaesthesia syndrome, Nail disorders, Muscle spasms, Renal impairment/ Renal failure, Pyrexia, Weight decreased.
See prescribing information for full details.
Interactions with drug transport systems
Effects of P-gp and breast cancer resistance protein (BCRP) inhibitors on afatinib: In vitro studies have demonstrated that afatinib is a substrate of P-gp and BCRP. When the strong P-gp and BCRP inhibitor ritonavir (200 mg twice a day for 3 days) was administered 1 hour before a single dose of 20 mg GIOTRIF, exposure to afatinib increased by 48% (area under the curve (AUC0-∞)) and 39% (maximum plasma concentration (Cmax)). In contrast, when ritonavir was administered simultaneously or 6 hours after 40 mg GIOTRIF, the relative bioavailability of afatinib was 119% (AUC0-∞) and 104% (Cmax) and 111% (AUC0-∞) and 105% (Cmax), respectively. Therefore, it is recommended to administer strong P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) using staggered dosing, preferably 6 hours or 12 hours apart from GIOTRIF.
Effects of P-gp inducers on afatinib: Pre-treatment with rifampicin (600 mg once daily for 7 days), a potent inducer of P-gp, decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) after administration of a single dose of 40 mg GIOTRIF. Strong P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital or St. John’s wort (Hypericum perforatum)) may decrease exposure to afatinib.
Effects of afatinib on P-gp substrates: Based on in vitro data, afatinib is a moderate inhibitor of P-gp. However, based on clinical data it is considered unlikely that GIOTRIF treatment will result in changes of the plasma concentrations of other P-gp substrates.
Interactions with BCRP: In vitro studies indicated that afatinib is a substrate and an inhibitor of the transporter BCRP. Afatinib may increase the bioavailability of orally administered BCRP substrates (including but not limited to rosuvastatin and sulfasalazine).
Food effect on afatinib
Co-administration of a high-fat meal with GIOTRIF resulted in a significant decrease of exposure to afatinib by about 50% in regard to Cmax and 39% in regard to AUC0-∞. This medicinal product should be administered without food.
Pregnancy and Lactation
Women of childbearing potential: As a precautionary measure, women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment. Adequate contraceptive methods should be used during therapy and for at least 1 month after the last dose.
Pregnancy: There are no or limited amount of data from the use of this medicinal product in pregnant women. The risk for humans is thus unknown. If used during pregnancy or if the patient becomes pregnant while or after receiving GIOTRIF, she should be informed of the potential hazard to the foetus.
Lactation: A risk to the breast-feeding child cannot be excluded. Mothers should be advised against breast-feeding while receiving this medicinal product.
See prescribing information for full details.
Symptoms: The highest dose of afatinib studied in a limited number of patients in Phase I clinical trials was 160 mg once daily for 3 days and 100 mg once daily for 2 weeks. The adverse reactions observed at these doses were primarily dermatological (rash/acne) and gastrointestinal events (especially diarrhoea). Overdose in 2 healthy adolescents involving the ingestion of 360 mg each of afatinib (as part of a mixed drug ingestion) was associated with adverse events of nausea, vomiting, asthenia, dizziness, headache, abdominal pain and elevated amylase (< 1.5 times ULN). Both individuals recovered from these adverse events.
Treatment: There is no specific antidote for overdose with this medicinal product. In cases of suspected overdose, this drug should be withheld and supportive care initiated. If indicated, elimination of unabsorbed afatinib may be achieved by emesis or gastric lavage.
Lactose: Contains lactose.
Storage: Store below 25°C. Store in the original package in order to protect from moisture and light. Following first opening of the aluminium pouch the blister tablets should be used within 14 days.
Before/after meal: This medicinal product should be administered without food.