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阿法替尼简介

阿法替尼英文说明书

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Afatinib 英文原版说明

Introduction

Antineoplastic agent; a second-generation inhibitor of receptor tyrosine kinases.

Uses for Afatinib DimaleateBrand nameGiotrif,Gilotrif,Xovoltib,妥复克)

Non-small Cell Lung Cancer (NSCLC)

First-line treatment of previously untreated metastatic NSCLC in patients with tumors positive for epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 substitution (L858R) mutations as detected by an FDA-approved diagnostic test (designated an orphan drug by FDA for this use).

Safety and efficacy not established in patients with EGFR mutations other than exon 19 deletion or exon 21 substitution.

Afatinib Dimaleate Dosage and Administration

General

·         Confirmation of EGFR mutation-positive (i.e., del19, L858R) NSCLC by an FDA-approved diagnostic test is necessary prior to initiating therapy.

·         Provide patients with antidiarrheal therapy (e.g., loperamide) for subsequent home use as needed.1 (See Diarrhea under Cautions.)

Administration

Oral Administration

Administer orally once daily.1 Administer on an empty stomach (at least 1 hour before or 2 hours after a meal).

Dosage

Available as afatinib dimaleate; dosage expressed in terms of afatinibBrand nameGiotrif,Gilotrif,Xovoltib,妥复克).

Adults

NSCLC
Oral

40 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 In the principal efficacy study, afatinib was continued for a median of 11 months.

Dosage Modification

Dosage reduction, temporary interruption, or permanent discontinuance of therapy may be necessary.

Permanently discontinue therapy in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions; interstitial lung disease; severe drug-induced hepatic impairment; persistent ulcerative keratitis; or symptomatic left ventricular dysfunction.1(See Warnings/Precautions under Cautions.) Also permanently discontinue therapy if severe or intolerable adverse reactions occur at a dosage of 20 mg daily.

Grade 3 or 4 Toxicity

If grade 3 or 4 toxicity occurs, temporarily interrupt afatinibBrand nameGiotrif,Gilotrif,Xovoltib,妥复克) therapy.When toxicity resolves completely or improves to grade 1, resume therapy at a reduced dosage (i.e., 10 mg less than the daily dosage used prior to the event).

Diarrhea

If grade 2 diarrhea persists for >48 hours or grade 3 or greater diarrhea occurs, temporarily interrupt afatinib therapy. When diarrhea improves to ≤grade 1, resume therapy at a reduced dosage (i.e., 10 mg less than the daily dosage used prior to the event). (See Diarrhea under Cautions.)

Dermatologic Toxicity

If intolerable or prolonged (lasting >7 days) grade 2 cutaneous reactions or grade 3 cutaneous reactions occur, temporarily interrupt afatinib therapy.1 When cutaneous reactions improve to ≤grade 1, resume therapy at a reduced dosage (i.e., 10 mg less than the daily dosage used prior to the event).

If life-threatening bullous, blistering, or exfoliating lesions occur, permanently discontinue therapy. (See Dermatologic Effects under Cautions.)

Nephrotoxicity

If grade 2 or greater nephrotoxicity occurs, temporarily interrupt afatinibBrand nameGiotrif,Gilotrif,Xovoltib,妥复克) therapy.1 When nephrotoxicity resolves completely, returns to baseline, or improves to grade 1, resume therapy at a reduced dosage (i.e., 10 mg less than the daily dosage used prior to the event).

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No adjustment of initial dosage needed.

Severe hepatic impairment (Child-Pugh class C): Monitor closely and adjust dosage if not tolerated.(See Hepatic Impairment under Cautions.)

Renal Impairment

Mild renal impairment (Clcr 60–89 mL/minute): No adjustment of initial dosage needed.

Moderate or severe renal impairment (Clcr ≤59 mL/minute): Monitor closely and adjust dosage if not tolerated. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.(See Geriatric Use under Cautions.)

Cautions for Afatinib Dimaleate

Contraindications

·         Manufacturer states none known.

Warnings/Precautions

Diarrhea

Diarrhea resulting in dehydration with or without renal impairment, sometimes fatal, reported. In principal efficacy study, diarrhea occurred in 96% and was severe (grade 3) in 15% of patients receiving afatinib. Diarrhea generally occurred within first 6 weeks of therapy.

If persistent or severe diarrhea occurs, temporarily interrupt therapy and reduce subsequent dosage.(See Diarrhea under Dosage and Administration.)

Provide patients with antidiarrheal therapy (e.g., loperamide) for subsequent home use as needed.Advise patients to take antidiarrheal agent at onset of diarrhea and until loose bowel movements have ceased for 12 hours.

Dermatologic Effects

Cutaneous reactions (i.e., rash, erythema, acneiform rash) reported in 90% of patients receiving afatinib.1 (See Advice to Patients.) Grade 3 cutaneous reactions (characterized by bullous, blistering, and exfoliating lesions) also reported.Grade 1–3 palmar-plantar erythrodysesthesia (hand-foot syndrome) also reported.

May manage afatinib-associated rash with topical or systemic corticosteroids, anti-infectives, or antihistamines.

If severe or persistent cutaneous reactions occur, temporarily interrupt therapy and reduce subsequent dosage.(See Dermatologic Toxicity under Dosage and Administration.)

Permanently discontinue afatinib in patients who develop life-threatening bullous, blistering, or exfoliating lesions.

Pulmonary Effects

Interstitial lung disease or interstitial lung disease-like events (e.g., lung infiltration, pneumonitis, ARDS, allergic alveolitis), sometimes fatal, reported. Incidence of interstitial lung disease reportedly higher in Asian patients compared with non-Asian patients.

Temporarily interrupt therapy if interstitial lung disease is suspected.1If diagnosis of interstitial lung disease is confirmed, permanently discontinue afatinib.

Hepatic Toxicity

Abnormal liver function tests, sometimes fatal, reported.

Perform liver function tests periodically during therapy.1Temporarily interrupt therapy in patients who develop worsening of liver function. Permanently discontinue afatinib in patients who develop severe hepatic impairment.

Ocular Effects

Keratitis (characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye), including grade 3 keratitis, reported.

Temporarily interrupt therapy if keratitis is suspected; if diagnosis of keratitis is confirmed, weigh potential benefit against risks of continued therapy.1 Temporarily interrupt or discontinue therapy in patients with confirmed ulcerative keratitis; permanently discontinue afatinib in patients with persistent ulcerative keratitis.

Use with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye.1 Contact lens use is a risk factor for development of keratitis and ulceration

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.Embryofetal toxicity (e.g., abortion) and teratogenicity demonstrated in animals.Pregnancy should be avoided during therapy and for at least 2 weeks after drug discontinuance. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard. (See Advice to Patients.)

Cardiovascular Effects

Left ventricular dysfunction reported. Permanently discontinue afatinib if symptomatic left ventricular dysfunction occurs.

Substantial (i.e., >20 msec) increases in mean corrected QT (QTc) interval not observed in patients with relapsed or refractory solid tumors receiving multiple doses of afatinib (50 mg once daily).

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.

Hepatic Impairment

Systemic exposure not affected by mild or moderate hepatic impairment (Child-Pugh class A or B).

Not studied in patients with severe hepatic impairment (Child-Pugh class C); therefore, monitor closely.(See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Median trough concentrations increased by mild or moderate renal impairment (Clcr 30–89 mL/minute).1(See Absorption: Special Populations, under Pharmacokinetics.) Closely monitor patients with moderate renal impairment (Clcr 30–59 mL/minute). (See Renal Impairment under Dosage and Administration.)

Not studied in patients with severe renal impairment (Clcr <30 mL/minute); monitor closely.

Common Adverse Effects

Diarrhea, rash/dermatitis acneiform, mucositis or stomatitis,paronychiadry skindecreased appetite,pruritus,epistaxis, weight loss, cystitis, cheilitis, pyrexia,rhinorrhea,conjunctivitis,1nausea,vomiting,fatigue,elevated AST/ALT concentrations,hypokalemia.

Does not inhibit or induce CYP isoenzyme 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro. CYP-mediated mechanisms play a minor role in overall metabolism.

Drugs Affecting Hepatic Microsomal Enzymes

CYP inhibitors or inducers: Clinically important pharmacokinetic interactions unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP substrates: Clinically important pharmacokinetic interactions unlikely.

Drugs Affecting the P-glycoprotein Transport System

P-gp inhibitors: Possible pharmacokinetic interaction (increased systemic exposure to afatinib).Reduce dosage of afatinib if not tolerated. (See Specific Drugs under Interactions.)

P-gp inducers: Possible pharmacokinetic interaction (decreased systemic exposure to afatinib).Increase dosage of afatinib as tolerated. (See Specific Drugs under Interactions.)

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Store in original container and protect from excessive humidity and light.

Actions

·         Covalently binds to the kinase domains of epidermal growth factor receptor (EGFR/human epidermal growth factor receptor type 1 [HER1]/ErbB1), HER2/ErbB2, and HER4/ErbB4, and irreversibly inhibits tyrosine kinase phosphorylation, resulting in downregulation of ErbB signaling.

·         Inhibits phosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR and cell lines expressing del19 or L858R mutations, including some with the secondary T790M mutation1 12 (which confers resistance to the first-generation tyrosine kinase inhibitors erlotinib and gefitinib).

·         Inhibits proliferation of cell lines that overexpress HER2 in vitro.

·         Inhibits tumor growth in mice with tumors overexpressing wild-type EGFR, HER2, or the EGFR L858R/T790M mutation.

·         Appears to be approximately 100 times more potent than gefitinib against EGFR L858R-T790M EGFR mutations and as potent as lapatinib against HER2 in vitro.

 

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