Afatinib

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).

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% (AUC_0-∞) and 22% (C_max) after administration of a single dose of 40 mg afatinib. 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.

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 afatinib, exposure to afatinib increased by 48% (area under the curve (AUC_0-∞)) and 39% (maximum plasma concentration (C_max)). In contrast, when ritonavir was administered simultaneously or 6 hours after 40 mg afatinib, the relative bioavailability of afatinib was 119% (AUC_0-∞) and 104% (C_max) and 111% (AUC_0-∞) and 105% (C_max), 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 afatinib.

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.

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.

Exposure to afatinib was found to be increased in patients with moderate or severe renal impairment. Adjustments to the starting dose are not necessary in patients with mild (eGFR 60-89 mL/min/1.73m²), moderate (eGFR 30-59 mL/min/1.73m²) or severe (eGFR 15-29 mL/min/1.73m²) renal impairment. Monitor patients with severe renal impairment (eGFR 15-29 mL/min/1.73m²) and adjust afatinib dose if not tolerated. Afatinib treatment in patients with eGFR <15 mL/min/1.73m² or on dialysis is not recommended.

Afatinib has not been studied in patients with severe (Child Pugh C) hepatic impairment. Treatment in this population is not recommended.

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. In the pivotal trials Grade 3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations were observed in 2.4% (LUX-Lung-3) and 1.6% (LUX-Lung 8) of patients with normal baseline liver tests treated with 40 mg/day. In LUX-Lung-3 Grade 3 ALT/AST elevations were about 3.5 fold higher in patients with abnormal baseline liver tests. There were no Grade 3 ALT/AST elevations in patients with abnormal baseline liver tests in LUX-Lung 8. 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.

Fertility studies in humans have not been performed with afatinib. Available non-clinical toxicology data have shown effects on reproductive organs at higher doses. Therefore, an adverse effect of this medicinal product on human fertility cannot be excluded.

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 patients treated with afatinib across all clinical trials (including 0.5% of patients with CTCAE Grade ≥3 ILD-like adverse reactions). 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.

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 and toxic epidermal necrolysis. Treatment with this medicinal product should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.

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.

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.

Gastrointestinal perforation, including fatalities, has been reported during treatment with afatinib in 0.2% of patients across all randomized controlled clinical trials. In the majority of cases, gastrointestinal perforation was associated with other known risk factors, including concomitant medications such as corticosteroids, NSAIDs, or anti-angiogenic agents, an underlying history of gastrointestinal ulceration, underlying diverticular disease, age, or bowel metastases at sites of perforation. In patients who develop gastrointestinal perforation while taking afatinib, treatment should be permanently discontinued.

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.

Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal harm. Animal studies with afatinib did not indicate direct or indirect harmful effects with respect to reproductive toxicity. Studies in animals have shown no signs of teratogenicity up to and including maternally lethal dose levels. Adverse changes were restricted to toxic dose levels. However, systemic exposures achieved in animals were either in a similar range or below the levels observed in patients.

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 afatinib, she should be informed of the potential hazard to the foetus.

Available pharmacokinetic data in animals have shown excretion of afatinib in milk. Based on this, it is likely that afatinib is excreted in human milk. A risk to the breast-feeding child cannot be excluded. Mothers should be advised against breast-feeding while receiving this medicinal product.

Fertility

Fertility studies in humans have not been performed with afatinib. Available non-clinical toxicology data have shown effects on reproductive organs at higher doses. Therefore, an adverse effect of this medicinal product on human fertility cannot be excluded.

Women of childbearing potential

As a precautionary measure, women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with afatinib. Adequate contraceptive methods should be used during therapy and for at least 1 month after the last dose.

Afatinib has minor influence on the ability to drive and use machines. During treatment, ocular adverse reactions (conjunctivitis, dry eye, keratitis) have been reported in some patients which may affect patients ability to drive or use machines.