TABLE OF CONTENTS
Afatinib is a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:
Empirical formula: C32H33ClFN5O11 - Molecular weight: 718.1 g/mol
Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic.
Afatinib tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively).
Inactive ingredients: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).
|2. INDICATIONS AND USAGE|
Afatinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
Limitation of Use: Safety and efficacy of afatinib have not been established in patients whose tumors have other EGFR mutations.
|3. DOSAGE AND ADMINISTRATION|
3.1 Patient Selection
Select patients for the first-line treatment of metastatic NSCLC with afatinib based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens [see Indications and Usage (2)]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
3.2 Recommended Dose
The recommended dose of afatinib is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take afatinib at least 1 hour before or 2 hours after a meal.
Do not take a missed dose within 12 hours of the next dose.
3.3 Dose Modification
Withhold afatinib for any drug-related adverse reactions of:
• NCI CTCAE* Grade 3 or higher
• Diarrhea of Grade 2 or higher persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions (5.1)]
• Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions (5.2)]
• Renal dysfunction of Grade 2 or higher
* National Cancer Institute Common Terminology Criteria for Adverse Events, v 3.0
Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute afatinib at a reduced dose, i.e., 10 mg per day less than the dose at which the adverse reaction occurred.
Permanently discontinue afatinib for:
• Life-threatening bullous, blistering, or exfoliative skin lesions [see Warnings and Precautions (5.2)]
• Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.3)]
• Severe drug-induced hepatic impairment [see Warnings and Precautions (5.4)]
• Persistent ulcerative keratitis [see Warnings and Precautions (5.5)]
• Symptomatic left ventricular dysfunction
• Severe or intolerable adverse reaction occurring at a dose of 20 mg per day
For patients who require therapy with a P-glycoprotein (P-gp) inhibitor, reduce afatinib daily dose by 10 mg if not tolerated. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [see Drug Interactions (7)].
For patients who require chronic therapy with a P-gp inducer, increase afatinib daily dose by 10 mg as tolerated. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer [see Drug Interactions (7)].
|5. WARNINGS AND PRECAUTIONS|
Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with afatinib (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks [see Adverse Reactions (6.1)]. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with afatinib, out of which 3 (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, withhold afatinib until diarrhea resolves to Grade 1 or less, and resume afatinib with appropriate dose reduction [see Dosage and Administration (3.3)]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.
5.2 Bullous and Exfoliative Skin Disorders
Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received afatinib across clinical trials [see Adverse Reactions (6.1)]. 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%. Discontinue afatinib in patients who develop life-threatening bullous, blistering, or exfoliating lesions [see Dosage and Administration (3.3)]. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold afatinib until the adverse reaction resolves to Grade 1 or less, and resume afatinib with appropriate dose reduction [see Dosage and Administration (3.3)].
5.3 Interstitial Lung Disease (ILD)
ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received afatinib across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of afatinib-treated patients.
Withhold afatinib during evaluation of patients with suspected ILD, and discontinue afatinib in patients with confirmed ILD [see Dosage and Administration (3.3)].
5.4 Hepatic Toxicity
In 3865 patients who received afatinib across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with afatinib.
Obtain periodic liver testing in patients during treatment with afatinib. Withhold afatinib in patients who develop worsening of liver function [see Dosage and Administration (3.3)]. In patients who develop severe hepatic impairment while taking afatinib, treatment should be discontinued.
Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with afatinib among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). Withhold afatinib during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with afatinib should be interrupted or discontinued [see Dosage and Administration (3.3)]. 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 [see Adverse Reactions (6.1)]. Contact lens use is also a risk factor for keratitis and ulceration.
5.6 Embryofetal Toxicity
Based on its mechanism of action, afatinib can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of afatinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking afatinib [see Use in Specific Populations (8.1 and 8.5)].
|6. ADVERSE REACTIONS|
The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Diarrhea [see Warnings and Precautions (5.1)]
• Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2)]
• Interstitial Lung Disease [see Warnings and Precautions (5.3)]
• Hepatic Toxicity [see Warnings and Precautions (5.4)]
• Keratitis [see Warnings and Precautions (5.5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety evaluation of afatinib is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving afatinib monotherapy at or above the recommended dose.
The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naïve afatinib-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received afatinib 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses.
The median exposure was 11.0 months for patients treated with afatinib and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the afatinib arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on afatinib and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (afatinib 70%; pemetrexed/cisplatin 72%).
Serious adverse reactions were reported in 29% of patients treated with afatinib. The most frequent serious adverse reactions reported in patients treated with afatinib were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in afatinib-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
Dose reductions due to adverse reactions were required in 57% of afatinib-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with afatinib were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%).
Discontinuation of therapy in afatinib-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in afatinib-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).
Clinical trials of afatinib excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the afatinib-treated group and as needed in the pemetrexed/cisplatin group. More afatinib-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).
Table 1. Adverse Reactions Reported in ≥10% of Afatinib-Treated Patients in Study 1
* None of the adverse reactions in this table were Grade 4 in severity
1 Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
2 Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform
3 Includes paronychia, nail infection, nail bed infection
Table 2. Adverse Reactions of Laboratory Abnormalities from the Investigations SOC Reported in ≥5% of Afatinib-Treated Patients in Study 1
1 Includes hypokalemia, blood potassium decreased
SOC=system organ class
|7. DRUG INTERACTIONS|
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
Oral administration of a P-gp inhibitor (ritonavir at 200 mg twice daily) 1 hour before administration of afatinib increased systemic exposure to afatinib by 48%. There was no change in afatinib exposure when ritonavir was administered simultaneously with or 6 hours after afatinib. 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 [see Dosage and Administration (3.3)].
Co-administration with oral dose of a P-gp inducer (rifampicin at 600 mg once daily for 7 days) decreased exposure to afatinib by 34%. 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 [see Dosage and Administration (3.3)].
|8. USE IN SPECIFIC POPULATIONS|
8.1 Usage in Pregnancy
Pregnancy Category D
Based on its mechanism of action, afatinib can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.6)].
Administration of afatinib to pregnant rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater during the period of organogenesis caused increased post implantation loss and, in animals showing maternal toxicity, abortion at late gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times the exposure by AUC at the recommended human dose of 40 mg daily) there were reduced fetal weights, and increases in the incidence of runts, as well as visceral and dermal variations. In an embryofetal development study in rats, there were skeletal alterations consisting of incomplete or delayed ossifications and reduced fetal weight at a dose of 16 mg/kg (approximately twice the exposure at the recommended human dose of 40 mg daily).
8.2 Nursing Mothers
It is not known whether afatinib is present in human milk. Afatinib was present in the milk of lactating rats at concentrations 80-150 times higher than those found in plasma from 1 to 6 hours after administration. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from afatinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.3 Pediatric Use
Safety and effectiveness of afatinib in pediatric patients have not been established.
8.4 Geriatric Use
Of the 3865 patients in the clinical studies of afatinib, 32% of patients were 65 years and older, while 7% were 75 years and older. No overall differences in safety were observed between patients 65 years and over and younger patients. In Study 1, 39% of the 345 patients were 65 years of age or older and 4% were 75 years or older. No overall differences in effectiveness were observed between patients 65 years and older and younger patients.
8.5 Females and Males of Reproductive Potential
Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with afatinib, and for at least 2 weeks after the last dose of afatinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking afatinib [see Use in Specific Populations (8.1)].
8.6 Renal Impairment
Afatinib has not been studied in patients with severely impaired renal function (creatinine clearance [CLcr] < 30 mL/min). Adjustments to the starting dose of afatinib are not considered necessary in patients with mild (CLcr 60-89 mL/min) renal impairment. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr < 30 mL/min) renal impairment and adjust afatinib dose if not tolerated.
8.7 Hepatic Impairment
Afatinib has not been studied in patients with severe (Child Pugh C) hepatic impairment. Adjustments to the starting dose of afatinib are not considered necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust afatinib dose if not tolerated.
Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of afatinib (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times upper limit of normal [ULN]). Both subjects recovered.
|10. MECHANISM OF ACTION|
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.
Afatinib demonstrated inhibition of autophosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR or those expressing selected EGFR exon 19 deletion mutations or exon 21 L858R mutations, including some with a secondary T790M mutation, at afatinib concentrations achieved, at least transiently, 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.
The effect of multiple doses of afatinib (50 mg once daily) on the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study.
Absorption and Distribution
Following oral administration of afatinib tablets, time to peak afatinib plasma concentrations (Tmax) is 2 to 5 hours. Maximum concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-∞) values increased slightly more than dose proportional in the range of 20 to 50 mg. The geometric mean relative bioavailability of 20 mg afatinib tablets was 92% as compared to an oral solution. In vitro binding of afatinib to human plasma proteins is approximately 95%.
A high-fat meal decreased Cmax by 50% and AUC0-∞ by 39% relative to the fasted condition [see Dosage and Administration (3.2)].
Metabolism and Elimination
Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal.
In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [14C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.
The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. Steady-state plasma concentrations are achieved within 8 days of repeat dosing of afatinib resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for Cmax.
Renal Impairment: The median trough afatinib plasma concentrations in patients with mild (CLcr 60-89 mL/min) and moderate (CLcr 30-59 mL/min) renal impairment were 27% and 85% higher than those in patients with normal renal function (CLcr ≥90 mL/min). Afatinib has not been studied in patients with severely impaired renal function (CLcr <30 mL/min) [see Use in Specific Populations (8.6)].
Hepatic Impairment: Afatinib is eliminated mainly by biliary/fecal excretion. Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of afatinib. Subjects with severe (Child Pugh C) hepatic dysfunction have not been studied [see Use in Specific Populations (8.7)].
Body Weight, Gender, Age, and Race: Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.
Effect of P-gp Inhibitors and Inducers on Afatinib: The effect of ritonavir dosing time relative to a single oral dose of afatinib was evaluated in healthy subjects taking 40 mg of afatinib alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after afatinib administration. The relative bioavailability for AUC0-∞ and Cmax of afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking afatinib. In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of afatinib, exposure to afatinib increased by 48% for AUC0-∞ and 39% for Cmax [see Drug Interactions (7)].
Pre-treatment with a potent inducer of P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC0-∞) and 22% (Cmax) [see Drug Interactions (7)].
P-glycoprotein (P-gp): Based on in vitro data, afatinib is a substrate and an inhibitor of P-gp.
Breast Cancer Resistance Protein (BCRP): Based on in vitro data, afatinib is a substrate and an inhibitor of the transporter BCRP.
Effect of CYP450 Enzyme Inducers and Inhibitors on Afatinib: In vitro data indicated that drug-drug interactions with afatinib due to inhibition or induction of CYP450 enzymes by concomitant medications are unlikely. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes. In humans, enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.
Effect of Afatinib on CYP450 Enzymes: Afatinib is not an inhibitor or an inducer of CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4) in cultured primary human hepatocytes. Therefore, afatinib is unlikely to affect the metabolism of other drugs that are substrates of CYP450 enzymes.
|13. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: GILOTRIF, by BOEHRINGER INGELHEIM.
b) Generic drugs: None.
2) How Supplied:
GILOTRIF tablets are available as follows:
40 mg: light blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T40” on one side and the Boehringer Ingelheim company symbol on the other side.
Unit of use bottles of 30 NDC: 0597-0138-30
30 mg: dark blue, film-coated, round, biconvex, bevel-edged tablets debossed with “T30” on one side and the Boehringer Ingelheim company symbol on the other side.
Unit of use bottles of 30 NDC: 0597-0137-30
20 mg: white to slightly yellowish, film-coated, round, biconvex, bevel-edged tablets debossed with “T20” on one side and the Boehringer Ingelheim company symbol on the other side.
Unit of use bottles of 30 NDC: 0597-0141-30
3) Storage and Handling:
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Dispense medication in the original container to protect from exposure to high humidity and light.