afatinib (Gilotrif)

Dosing and uses of Gilotrif (afatinib)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 20mg
• 30mg
• 40mg

 

Non-Small Cell Lung Cancer

40 mg PO qDay 1 hr ac or 2 hr pc

Administer until disease progression or inability to tolerate drug

Indications

• First-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test
• Metastatic squamous NSCLC which has progressed after platinum-based chemotherapy

 

Dosage modifications

Withhold dose for any drug-related adverse reactions of:

• NCI CTCAE Grade 3 or higher
• Diarrhea Grade 2 or higher persisting for 2 or more consecutive days while taking anti-diarrhea medication
• Cutaneous reactions Grade 2 that are prolonged (>7 days) or intolerable
• Renal dysfunction Grade 2 or higher
• Decrease dose (ie, 10 mg/day less than previous dose) and resume treatment when adverse reaction fully resolves, returns to baseline, or improves to Grade 1

Permanently discontinue for:

• Life-threatening bullous, blistering, or exfoliative skin lesions
• Confirmed interstitial lung disease
• Severe drug-induced hepatic impairment
• Persistent ulcerative keratitis
• Symptomatic left ventricular dysfunction
• Severe or intolerable adverse reaction occurring at a dose of 20 mg/day

Coadministration with P-gp inhibitors

• For patients who require therapy with a P-gp inhibitor, reduce afatinib daily dose by 10 mg if not tolerated
• Resume previous dose after P-gp inhibitor is discontinued as tolerated

Coadministration with P-gp inducers

• 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 P-gp inducer is discontinued

Renal impairment

• Mild (CrCl 60-89 mL/min): Adjustment to starting dose not required
• Moderate (CrCl 30-59 mL/min or severe (CrCl <30 mL/min): Closely monitor and adjust dose if not tolerated

Hepatic impairment

• Mild-to-moderate (Child Pugh A or B): Adjustment to starting dose not required
• Severe (Child Pugh C): Closely monitor and adjust dose if not tolerated

 

Dosing Considerations

Safety and efficacy have not been established in tumors with other EGFR mutations than those listed in the approved indication

Afatinib was approved concurrently with the diagnostic companion test, therascreen EGFR RGQ PCR Kit

Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: https://www.fda.gov/CompanionDiagnostics

 

CNS Tumors (Orphan)

Orphan designation for treatment of malignant brain and CNS tumors

Sponsor

• Boehringer Ingelheim Pharmaceuticals, Inc; 900 Ridgebury Road, PO Box 368; Ridgefield, CT 06877-0368

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Gilotrif (afatinib) adverse (side) effects

All grades included unless otherwise noted

 

>10%

Diarrhea (75-96%)

Rash/dermatitis acneiform (90%)

Stomatitis (71%)

Paronychia (58%)

Dry skin (31%)

Decreased appetite (29%)

Pruritus (21%)

Epistaxis (17%)

Weight decreased (17%)

Diarrhea, grades 3 or 4 (11-15%)

Cystitis (13%)

Cheilitis (12%)

Pyrexia (12%)

Rhinorrhea (11%)

Conjunctivitis (11%)

Increased ALT (11%)

Hypokalemia (11%)

 

1-10%

Increased AST (8%)

Interstitial lung disease (1.5%)

 

<1%

Keratitis (0.8%)

 

Postmarketing Reports

Nausea/vomiting

Pancreatitis

 

Warnings

Contraindications

None

 

Cautions

May cause diarrhea that results in dehydration with or without renal impairment; some reported cases were fatal; withhold therapy for severe and prolonged diarrhea not responsive to antidiarrheal agents

Postmarketing cases consistent with toxic epidermal necrolysis (TEN), including bullous and exfoliative skin disorders, and Stevens Johnson syndrome (SJS) reported; discontinue if life-threatening bullous, blistering, or exfoliating lesions occur; withhold therapy for severe and prolonged cutaneous reactions

May increase risk for sunburn/phototoxicity; may worsen rash or acne; caution patients to limit sun exposure and where sunscreen and protective clothing

Interstitial lung disease (ILD) or ILD-like adverse reactions reported (eg, lung infiltration, pneumonitis, acute respiratory distress syndrome, alveolitis allergy) occurred in 1%, of these, 0.4% were fatal; discontinue therapy if ILD diagnosed

Hepatotoxicity reported; monitor with periodic liver testing; withhold or discontinue therapy for severe or worsening liver tests

Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8%; withhold or discontinue therapy for confirmed ulcerative keratitis

Based on its mechanism of action, afatinib can cause fetal harm; advise pregnant women and females of reproductive potential of potential risk to fetus and to use effective contraception

 

Pregnancy and lactation

Pregnancy category: D; Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose

Lactation: Unknown if distributed in human breast milk; 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

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Gilotrif (afatinib)

Mechanism of action

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

Demonstrates 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

In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2

 

Absorption

Bioavailability: 92%

Peak plasma time: 2-5 hr

High fat meal decreases Cmax by 50% and AUC by 39% relative to the fasted condition (take on empty stomach)

 

Distribution

Protein bound: 95%

 

Metabolism

Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimaL

 

Elimination

Half-life: 37 hr

Excretion: 85% feces; 4% urine

 

Administration

Oral Administration

Take PO on empty stomach, at least 1 hr before or 2 hr after a meaL