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 Non-Resistant EGFR Mutation-Positive Metastatic NSCLC: Select patients for first line treatment of metastatic NSCLC with Afatinib based on the presence of non-resistant EGFR 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.

Renal impairment: 30 mg orally, once daily in patients with severe renal impairment.

Instruct patients to take Afatinib at least 1 hour before or 2 hours after a meal.

Co-administration of P-gp inhibitors can increase afatinib exposure. Reduce Afatinib by 10 mg per day if not tolerated. Co-administration of chronic P-gp inducers orally can decrease afatinib exposure. Increase Afatinib by 10 mg per day as tolerated.

Most common adverse reactions (≥20%) were diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus.

Based on findings from animal studies and its mechanism of action, Afatinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Afatinib in pregnant women. Administration of afatinib to pregnant rabbits during organogenesis at exposures approximately 0.2 times the exposure in humans at the recommended dose of 40 mg daily resulted in embryotoxicity and, in rabbits showing maternal toxicity, increased abortions at late gestational stages [see Data]. Advise a pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

There are no data on the presence of afatinib in human milk or its effects on the breastfed infant or on milk production. Afatinib was present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants from Afatinib, advise a lactating woman not to breastfeed during treatment with Afatinib and for 2 weeks after the final dose.

Diarrhea: Diarrhea may result in dehydration and renal failure. Withhold afatinib for severe and prolonged diarrhea not responsive to anti-diarrheal agents.

Bullous and exfoliative skin disorders: Severe bullous, blistering, and exfoliating lesions occurred in 0.2% of patients. Discontinue for life-threatening cutaneous reactions. Withhold afatinib for severe and prolonged cutaneous reactions.

Interstitial lung disease (ILD): Occurs in 1.6% of patients. Withhold afatinib for acute onset or worsening of pulmonary symptoms. Discontinue afatinib if ILD is diagnosed.

Hepatic toxicity: Fatal hepatic impairment occurs in 0.2% of patients. Monitor with periodic liver testing. Withhold or discontinue afatinib for severe or worsening liver tests.

Keratitis: Occurs in 0.7% of patients. Withhold afatinib for keratitis evaluation. Withhold or discontinue afatinib for confirmed ulcerative keratitis.

Embryo-fetal toxicity: Can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus and to use effective contraception.

Tyrosine Kinase Inhibitor

Store at 25°C; excursions permitted to 15°-30°C. Dispense medication in the original container to protect from exposure to high humidity and light.