Afatinib Dimaleate

Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions.

Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.

Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

Patient Selection for EGFR Mutation-Positive Metastatic NSCLC: Patients should be selected for first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens.

Recommended Dose: The recommended dose of Afatinib is 40 mg orally, once daily until disease progression or no longer tolerated by the patient.

Severe Renal Impairment: The recommended dose of Afatinib in patients with severe renal impairment (estimated glomerular filtration rate 15 to 29 mL/min /1.73 m²) is 30 mg orally, once daily. Afatinib should be taken at least 1 hour before or 2 hours after a meal. A missed dose should not be taken within 12 hours of the next dose. Or, as directed by the registered physicians.

Pediatric Use: Safety and effectiveness of Afatinib in pediatric patients have not been established.

Effect of P-glycoprotein (P-gp) Inhibitors and Inducers: Concomitant taking of P- gp inhibitors (including but not limited to Ritonavir, Cyclosporine A, Ketoconazole, Itraconazole, Erythromycin, Verapamil, Quinidine, Tacrolimus, Nelfinavir, Saquinavir, and Amiodarone) with Afatinib can increase exposure to Afatinib. Concomitant taking of P- gp inducers (including but not limited to Rifampicin, Carbamazepine, Phenytoin, Phenobarbital, and St. John's wort) with Afatinib can decrease exposure to Afatinib.

It is contraindicated in patients with known hypersensitivity to Afatinib or any other components of this product.

• Diarrhea
• Bullous and Exfoliative Skin Disorders
• Interstitial Lung Disease
• Hepatic Toxicity
• Keratitis

Afatinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Afatinib in pregnant women. There are no data on the presence of Afatinib in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in nursing infants from Afatinib, a lactating woman should be advised not to breastfeed during treatment with Afatinib and for 2 weeks after the final dose.

Diarrhea: Diarrhea has resulted in dehydration with or without renal impairment across the clinical experience; some cases were fatal. Grade3-4 diarrhea occurred in 697 (16%) of the 4257 patients who received Afatinib across 44 clinical trials. In Study 1, diarrhea occurred in 96% of patients treated with Afatinib (n=229), of which 15% were Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6% of patients treated with Afatinib, of which 1.3% were Grade 3. For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours, or greater than or equal to Grade 3 diarrhea, Afatinib should be withheld until diarrhea resolves to Grade 1 or less, and resume Afatinib with appropriate dose reduction.

Bullous and Exfoliative Skin Disorders: Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions, occurred in 0.2% of the 4257 patients who received Afatinib across clinical trials. In Study 1, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Afatinib should be discontinued in patients who develop life-threatening bullous, blistering, or exfoliating lesions.

Interstitial Lung Disease (ILD): Interstitial lung disease or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.6% of the 4257 patients who received Afatinib across clinical trials; of these, 0.4% were fatal. Afatinib should be withheld during evaluation of patients with suspected ILD, and Afatinib should be discontinued in patients with confirmed ILD.

Hepatic Toxicity: In 4257 patients who received Afatinib across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with Afatinib, of which 3.5% had Grade 3-4 liver test abnormalities. Periodic liver testing should be obtained in patients during treatment with Afatinib. Afatinib should be withheld in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking Afatinib, treatment should be discontinued.

Keratitis: Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.7% of patients treated with Afatinib among 4257 patients across clinical trials, of which 0.05% of patients experienced Grade 3 keratitis. Keratitis was reported in 2.2% patients in Study 1, with Grade 3 in 0.4%. Afatinib should be withheld during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with Afatinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Afatinib 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.

Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of Anib (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase. Both subjects recovered.

Tyrosine Kinase Inhibitor

Store below 30°C in a cool and dry place, away from sunlight. Keep out of reach of children.