Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Gilotrif: 20 mg
Gilotrif: 30 mg, 40 mg [contains fd&c blue #2 (indigotine)]
Mechanism of Action
Afatinib is a highly selective tyrosine kinase inhibitor that covalently binds to EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) to irreversibly inhibit tyrosine kinase autophosphorylation and downregulate ErbB signaling. Certain EGFR mutations (including nonresistant mutations) result in increased receptor autophosphorylation, leading to receptor activation (sometimes without ligand binding), and may support NSCLC cell proliferation. Nonresistant mutations occur in exons constituting the EGFR kinase domain that lead to increased receptor activation; efficacy is predicted by tumor shrinkage and/or inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation. The most common mutations are exon 21 L858R substitutions and exon 19 deletions. Afatinib inhibits autophosphorylation and/or proliferation (in vitro) in cell lines expressing both wild-type EGFR and selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common nonresistant mutations. Additionally, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.
Decreased with high-fat meals
Covalently adducted to proteins and nucleophilic small molecules (minimal enzymatic metabolism) (Wind 2013); ~2% of a dose is metabolized by FMO3
Feces (85%); urine (4%); primarily as unchanged drug
Time to Peak
2 to 5 hours
Use in Specific Populations
Special Populations: Renal Function Impairment
A small pharmacokinetic study demonstrated a 50% increase and a 22% increase in mean AUCinf in patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2) and moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2), respectively, as compared to patients with normal renal function (eGFR 90 mL/minute/1.73 m2 or higher). Cmax was 22% higher in patients with severe renal impairment and was comparable in patients with moderate renal impairment and patients with normal renal function.
Use: Labeled Indications
Non-small cell lung cancer, metastatic, EGFR mutation-positive: First-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have nonresistant epidermal growth factor receptor (EGFR) mutations as detected by an approved test.
Limitations of use: Safety and efficacy have not been established in patients whose tumors express resistant EGFR mutations.
Non-small cell lung cancer, metastatic squamous: Treatment of previously treated metastatic squamous cell NSCLC that has progressed following platinum-based chemotherapy.
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Hypersensitivity to afatinib or any component of the formulation.
Dosage and Administration
Non-small cell lung cancer (NSCLC), metastatic, with nonresistant EGFR mutations: Oral: 40 mg once daily until disease progression or unacceptable toxicity
NSCLC, metastatic squamous (previously treated): Oral: 40 mg once daily until disease progression or unacceptable toxicity
Missed doses: Do not take a missed dose within 12 hours of next dose.
Dosage adjustment for concomitant therapy:
P-gp inhibitors: If concomitant therapy is not tolerated, reduce afatinib daily dose by 10 mg. Upon discontinuation of the P-gp inhibitor, resume previous dose as tolerated.
P-gp inducers: Increase afatinib daily dose by 10 mg as tolerated if on chronic concomitant therapy with a P-gp inducer. Resume previous dose 2 to 3 days after discontinuation of P-gp inducer.
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Note: Permanently discontinue for intolerability or severe reaction occurring at a dose of 20 mg daily.
Cardiovascular: Permanently discontinue for symptomatic left ventricular dysfunction.
Dermatologic: Withhold therapy for prolonged (>7 days) or intolerable grade 2 or higher cutaneous reactions. Upon improvement to baseline or ≤ grade 1, resume therapy at 10 mg per day less than previous dose. Discontinue permanently for life-threatening bullous, blistering, or exfoliating skin lesions, as well as for suspected toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS).
Grade 2 that persists for ≥2 consecutive days despite antidiarrheal therapy: Interrupt therapy until fully resolves, returns to baseline, or improves to ≤ grade 1, then resume with the dose reduced by 10 mg per day less than previous dose.
Grade 3 or higher: Interrupt therapy until resolution to ≤ grade 1, then resume at 10 mg per day less than previous dose.
GI perforation: Discontinue permanently.
Ocular: Interrupt therapy for suspected keratitis; consider discontinuation if diagnosis of ulcerative keratitis is confirmed. Permanently discontinue for persistent ulcerative keratitis.
Pulmonary: Interrupt therapy for suspected interstitial lung disease (ILD); permanently discontinue if diagnosis is confirmed.
Other toxicity: Grade 3 or higher adverse reactions: Withhold therapy for ≥ grade 3 adverse reactions. Upon improvement to baseline or ≤ grade 1, resume therapy at 10 mg per day less than previous dose.
Oral: Administer ≥1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose.
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Dispense in original bottle; protect from high humidity and light.
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination
Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy
Nelfinavir: May increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10 mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer nelfinavir simultaneously with or after the dose of afatinib. Consider therapy modification
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of P-gp inducers, increase afatinib dose by 10 mg as tolerated; reduce to original afatinib dose 2-3 days after stopping P-gp inducers. Per Canadian labeling: avoid combination if possible. Consider therapy modification
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification
PHENobarbital: May decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of phenobarbital, increase afatinib dose by 10 mg as tolerated; reduce to original afatinib dose 2-3 days after stopping phenobarbital. Per Canadian labeling: avoid combination if possible. Consider therapy modification
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy
Primidone: May decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of primidone, increase afatinib dose by 10 mg as tolerated; reduce to original afatinib dose 2-3 days after stopping primidonel. Per Canadian labeling: avoid combination if possible. Consider therapy modification
Saquinavir: May increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10 mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer saquinavir simultaneously with or after the dose of afatinib. Consider therapy modification
Tacrolimus (Systemic): May increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10 mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer tacrolimus simultaneously with or after the dose of afatinib. Consider therapy modification
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy
Dermatologic: Acneiform eruption (≤90%), erythema of skin (≤90%), skin rash (≤90%), paronychia (11% to 58%), xeroderma (31%), pruritus (10% to 21%), cheilitis (12%)
Endocrine & metabolic: Decreased serum potassium (11% to 30%), weight loss (17%)
Gastrointestinal: Diarrhea (75% to 96%), stomatitis (30% to 71%; grade 3: 9%; grades 3/4: 4%), decreased appetite (25% to 29%), nausea (21% to 25%), vomiting (13% to 23%)
Genitourinary: Cystitis (13%)
Hematologic & oncologic: Lymphocytopenia (38%; grades 3/4: 9%), decreased white blood cell count (12%; grades 3/4: 1%)
Hepatic: Increased serum alanine aminotransferase (10% to 54%), increased serum alkaline phosphatase (34% to 51%), increased serum aspartate aminotransferase (7% to 46%), abnormal hepatic function tests (6% to 18%), increased serum bilirubin (3% to 16%)
Ophthalmic: Conjunctivitis (11%)
Renal: Decreased creatinine clearance (49%)
Respiratory: Epistaxis (17%), rhinorrhea (11%)
Miscellaneous: Fever (12%)
1% to 10%:
Cardiovascular: Ventricular dysfunction (2%)
Central nervous system: Fatigue (2%)
Dermatologic: Nail disease (3% to 9%), palmar-plantar erythrodysesthesia (2% to 7%)
Gastrointestinal: Severe diarrhea (5% to 6%), severe vomiting (5%)
Endocrine & metabolic: Hypokalemia (2%)
Ophthalmic: Keratitis (≤2%)
Respiratory: Pneumonia (7%), dyspnea (2% to 3%), interstitial pulmonary disease (≤2%), pulmonary toxicity (≤1%)
<1%, postmarketing, and/or case reports: Acute renal function, bullous rash, gastrointestinal perforation, local skin exfoliation, pancreatitis, physical health deterioration, respiratory failure, sepsis, skin blister, Stevens-Johnson syndrome, toxic epidermal necrolysis
Concerns related to adverse effects:
- Cardiovascular toxicity: Decreases from baseline in left ventricular ejection fraction (LVEF) were noted in some patients receiving afatinib. Patients with abnormal LVEF or a significant cardiac history were excluded from clinical trials; use with caution in patients with cardiac risk factors and/or decreased LVEF. Permanently discontinue in patients who develop symptomatic left ventricular dysfunction.
- Dermatologic toxicity: Cutaneous reactions (eg, acneiform rash, erythema, rash) are common; grade 3 reactions (characterized by bullous, blistering, and exfoliating lesions) and palmar-plantar erythrodysesthesia syndrome were also seen in clinical trials. Cases of skin reactions consistent with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported; SJS and TEN result from a mechanism that is distinct and separate from the bullous skin toxicity typically observed with EGFR inhibitor therapy. Dermatologic toxicity may require therapy interruption and dosage reduction; discontinue if life-threatening bullous, blistering, or exfoliating lesions occur or for suspected SJS or TEN. Patients should be cautioned to avoid sun exposure and/or utilize adequate sun protection.
- GI toxicity: In clinical trials, diarrhea (including grade 3 and 4 events) and stomatitis frequently occurred in patients treated with afatinib; diarrhea was observed in the majority of patients and typically appeared within the first 6 weeks of therapy. Dehydration and renal impairment may occur as a consequence of diarrhea; monitor closely. Patients may require antidiarrheal therapy (eg, loperamide); initiate at the onset of diarrhea and continue until free of loose bowel movements for 12 hours. May necessitate therapy interruption and dosage reduction. GI perforations (some fatal) have been reported; risk may be increased in older patients, patients with a history of GI ulceration, underlying diverticular disease or bowel metastases, or with concomitant use of corticosteroids, NSAIDs, or anti-angiogenic agents. Permanently discontinue afatinib in patients who develop GI perforation.
- Hepatotoxicity: Hepatic function test abnormalities (some fatal) were observed in clinical trials. Monitor liver function tests periodically; may require therapy interruption and dosage reduction. Discontinue if severe hepatic impairment occurs during therapy.
- Ocular toxicity: Keratitis (including rare grade 3 events) was reported rarely in clinical trials; monitor for signs/symptoms of keratitis (eg, acute or worsening eye inflammation, blurred vision, eye pain, lacrimation, light sensitivity, red eye). Interrupt therapy in patients with suspected keratitis; if diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue afatinib (permanently discontinue for persistent ulcerative keratitis). Use with caution in patients with a history of keratitis, severe dry eye, ulcerative keratitis, or who wear contact lenses (risk factor for keratitis and ulceration).
- Paronychia: Paronychia requiring dose reduction and discontinuation of therapy has been observed.
- Pulmonary toxicity: Interstitial lung disease (ILD) or ILD-like reactions occurred in a small percentage of patients treated with afatinib (some fatal). ILD incidence appeared to be higher in Asian compared with non-Asian patients. Monitor closely for signs/symptoms of ILD (eg, acute respiratory distress syndrome, allergic alveolitis, lung infiltration, pneumonitis). Interrupt therapy for suspected ILD; discontinue therapy with confirmed diagnosis.
- Hepatic impairment: Use in severe hepatic impairment (Child-Pugh class C) has not been studied; closely monitor patients with severe impairment, may require dosage adjustments if not tolerated.
- Renal impairment: Dosage reduction is recommended in patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2).
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage forms specific issues:
- Lactose: Formulation may contain lactose.
- Appropriate use: For first-line therapy, safety and efficacy have not been established in patients with non-small cell lung cancer whose tumors express resistant EGFR mutations. Information on EGFR mutation testing is available at www.fda.gov/CompanionDiagnostics. Increased mortality has been observed in a clinical trial evaluating afatinib in combination with vinorelbine for HER2-positive metastatic breast cancer (not an approved use). This combination was also associated with a higher incidence of adverse events (eg, diarrhea, rash), as well as fatalities due to infection and cancer progression. Afatinib should not be used in combination with vinorelbine for the treatment of HER2-positive metastatic breast cancer.
EGFR mutation status (for first-line therapy); liver and renal function (periodically); monitor for skin toxicity, diarrhea, signs/symptoms of dehydration; monitor for signs/symptoms of interstitial lung disease (eg, acute respiratory distress syndrome, allergic alveolitis, lung infiltration, pneumonitis) and keratitis (eg, acute or worsening eye inflammation, blurred vision, eye pain, lacrimation, light sensitivity, red eye). Consider left ventricular ejection fraction assessment prior to and during therapy in patients with cardiac risk factors or conditions that may impair left ventricular function. Monitor adherence.
Based on animal reproduction studies and on the mechanism of action, afatinib may cause fetal harm if used during pregnancy. Women of reproductive potential should use highly effective contraception during therapy and for at least 2 weeks after the last afatinib dose.
What is this drug used for?
- It is used to treat lung cancer.
Frequently reported side effects of this drug
- Dry skin
- Dry lips
- Lack of appetite
- Mouth sores
- Mouth irritation
- Runny nose
- Weight loss
- Skin or nail changes
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
- Shortness of breath
- Excessive weight gain
- Swelling of arms or legs
- Loss of strength and energy
- Abnormal heartbeat
- Vision changes
- Eye pain
- Severe eye irritation
- Sensitivity to light
- Painful urination
- Redness or irritation of palms or soles of feet
- Severe abdominal pain
- Severe or persistent diarrhea
- Skin changes
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
- Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
- Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.