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Afatinib

Pronunciation

(a FA ti nib)

Index Terms

  • Afatinib Dimaleate
  • BIBW 2992

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Gilotrif: 20 mg

Gilotrif: 30 mg, 40 mg [contains fd&c blue #2 (indigotine)]

Brand Names: U.S.

  • Gilotrif

Pharmacologic Category

  • Antineoplastic Agent, Epidermal Growth Factor Receptor (EGFR) Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Highly selective blocker of the ErbB family, including EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4); covalently and irreversibly binds to the intracellular tyrosine kinase domain, resulting in tumor growth inhibition and tumor regression. Inhibits autophosphorylation and proliferation (in vitro) in cell lines expressing both wild-type EGFR and selected EGFR mutations.

Absorption

Decreased with high-fat meals

Metabolism

Covalently adducted to proteins and nucleophilic small molecules (minimal enzymatic metabolism) (Wind, 2013)

Excretion

Feces (85%); urine (4%); primarily as unchanged drug

Time to Peak

2 to 5 hours

Half-Life Elimination

37 hours

Protein Binding

~95%

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 as compared to patients with normal renal function.

Use: Labeled Indications

US labeling:

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 epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an approved test.

Limitations of use: Safety and efficacy have not been established in patients whose tumors express EGFR mutations other than exon 19 deletion or exon 21 (L858R) substitution.

Non-small cell lung cancer, metastatic squamous: Treatment of previously treated metastatic squamous cell NSCLC which has progressed following platinum-based chemotherapy.

Canadian labeling:

Non-small cell lung cancer, metastatic, EGFR mutation-positive: Treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a validated test.

Limitations of use: Safety and efficacy have not been established in patients whose tumors express EGFR mutations other than exon 19 deletion or exon 21 (L858R) substitution.

Contraindications

US labeling: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to afatinib or any component of the formulation.

Dosing: Adult

Non-small cell lung cancer (NSCLC), metastatic, with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations: Oral: 40 mg once daily until disease progression or unacceptable toxicity

NSCLC, metastatic squamous: Oral: 40 mg once daily until disease progression or unacceptable toxicity

Missed doses:

US labeling: Do not take a missed dose within 12 hours of next dose

Canadian labeling: Do not take a missed dose within 8 hours of next dose

Dosage adjustment for concomitant therapy:

US labeling:

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.

Canadian labeling: Avoid concurrent use with strong P-gp inhibitors or inducers. If concurrent use with a P-gp inhibitor is necessary, administer simultaneously with or after afatinib; monitor closely for adverse effects. The manufacturer labeling does not provide specific recommendations when concurrent use of a P-gp inducer is necessary.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Note: The manufacturer recommends using the Modification of Diet in Renal Disease (MDRD) formula to estimate the glomerular filtration rate (eGFR).

Preexisting impairment:

eGFR >30 mL/minute/1.73 m2: No dosage adjustment is necessary.

eGFR 15 to 29 mL/minute/1.73 m2: Reduce dose to 30 mg once daily. The Canadian labeling recommends avoiding use if CrCl <30 mL/minute.

eGFR <15 mL/minute/1.73 m2 and hemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). The Canadian labeling recommends avoiding use if CrCl <30 mL/minute.

Renal toxicity during treatment: If ≥ grade 2 renal toxicity occurs, withhold therapy. Upon improvement to baseline or ≤ grade 1, resume therapy at 10 mg per day less than previous dose.

Dosing: Hepatic Impairment

Preexisting mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment is necessary.

Preexisting severe impairment (Child-Pugh class C):

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); closely monitor and adjust dose if necessary.

Canadian labeling: Avoid use.

Hepatotoxicity during treatment: Withhold therapy for ≥ grade 3 hepatic dysfunction. Upon improvement to baseline or ≤ grade 1, resume therapy at 10 mg per day less than previous dose. Permanently discontinue for severe afatinib-induced hepatic impairment.

Dosing: Adjustment for Toxicity

Note: Permanently discontinue for intolerability or severe reaction occurring at a dose of 20 mg daily. The Canadian labeling recommends permanently discontinuing therapy for toxicities that do not resolve to ≤ grade 1 within 14 days of therapy interruption.

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 exfoliative skin lesions, as well as for suspected toxic epidermal necrolysis (TEN) or Stevens Johnson syndrome (SJS).

Gastrointestinal:

Diarrhea: Grade 2 or higher diarrhea that persists for ≥2 consecutive days despite antidiarrheal therapy: Interrupt therapy until resolution to ≤ grade 1, then resume at 10 mg per day less than previous dose.

Nausea/vomiting: Canadian labeling (not in US labeling): Intolerable grade 2 or persistent (≥7 days) nausea/vomiting despite antiemetic therapy: Interrupt therapy until resolution to ≤ grade 1, then resume at 10 mg per day less than previous dose.

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.

Other poorly tolerated grade 2 adverse reactions persisting ≥7 days: Canadian labeling (not in US labeling): Interrupt therapy until resolution to ≤ grade 1, then resume at 10 mg per day less than previous dose.

Administration

US labeling: Administer orally at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose. Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single-gloving for administration of an intact tablet (NIOSH 2014).

Canadian labeling: Administer orally at least 1 hour before or 3 hours after a meal. Do not take a missed dose within 8 hours of the next dose. Swallow whole with water.

Storage

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.

Drug Interactions

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

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 10mg 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: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Adverse Reactions

>10%:

Dermatologic: Acneiform eruption (≤70% to 90%; grade 3: ≤16%), skin rash (≤70% to 90%; grade 3: ≤16%), paronychia (11% to 58%), xeroderma (31%), pruritus (10% to 21%), cheilitis (12%)

Endocrine & metabolic: Decreased serum potassium (11% to 30%), weight loss (17%), hypokalemia (11%)

Gastrointestinal: Diarrhea (75% to 96%; grade 3: 15%; grades 3/4: 11% to 16%), stomatitis (30% to 71%), decreased appetite (25% to 29%), nausea (21% to 25%), vomiting (13% to 23%)

Genitourinary: Cystitis (13%)

Hematologic & oncologic: Abnormal lymphocytes (decreased: 38%; grades 3/4: 9%), decreased white blood cell count (12%; grades 3/4: 1%)

Hepatic: Increased serum ALT (10% to 54%; grades 3/4: 1% to 2%), increased serum alkaline phosphatase (34% to 51%; grades 3/4: 2% to 3%), increased serum AST (7% to 46%; grades 3/4: 1% to 3%), abnormal hepatic function tests (6% to 18%; grades 3/4: ≤4%), increased serum bilirubin (3% to 16%; grades 3/4: ≤1%)

Ophthalmic: Conjunctivitis (11%)

Renal: Decreased creatinine clearance (49%; grades 3/4: 2%)

Respiratory: Epistaxis (17%), rhinorrhea (11%)

Miscellaneous: Fever (12%)

1% to 10%:

Central nervous system: Fatigue (<2%)

Dermatologic: Palmar-plantar erythrodysesthesia (2% to 7%)

Ophthalmic: Keratitis (≤2%; grade 3: <1%)

Renal: Renal insufficiency (6%; grade 3: >1%)

Respiratory: Interstitial pulmonary disease (2%; grades 3/4: ≤1%), dyspnea (<2%)

Frequency not defined:

Endocrine & metabolic: Dehydration

Infection: Sepsis

Renal: Acute renal failure

Respiratory: Pneumonia

Miscellaneous: Physical health deterioration

<1% (Limited to important or life-threatening): Pancreatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Warnings/Precautions

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.

• Dermatologic toxicity: Cutaneous reactions (eg, acneiform rash, erythema, and 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 which 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.

• Gastrointestinal 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. The Canadian labeling recommends avoiding use in patients with GI disorders associated with diarrhea (eg, Crohn disease, malabsorption).

• 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 and consider discontinuation if diagnosis of ulcerative keratitis is confirmed (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 lens (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 as compared to 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.

Disease-related concerns:

• 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. The Canadian labeling does not recommend use in severe impairment.

• Renal impairment: Dosage reduction is recommended in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/minute/1.73 m2). The Canadian labeling does not recommend use in severe impairment.

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: Contains lactose; Canadian labeling recommends avoiding use in patients with hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Appropriate use: Safety and efficacy have not been established in patients with non-small cell lung cancer whose tumors express EGFR mutations other than exon 19 deletion or exon 21 (L858R) substitution. 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.

Monitoring Parameters

EGFR mutation status; 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.

Pregnancy Considerations

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 treatment has been discontinued.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience itching, dry skin, dry lips, acne, lack of appetite, nausea, vomiting, mouth sores, nosebleed, rhinorrhea, weight loss, or skin or nail changes. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, 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, painful irritation, sensitivity to light, severe skin irritation, redness or irritation of palms or soles of feet, severe diarrhea, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), or signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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