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Gilotrif

Generic Name: Afatinib Dimaleate
Class: Antineoplastic Agents
Chemical Name: (2E) - N - [4 - [(3 - Chloro - 4 - fluorophenyl)amino] - 7 - [[(3S) - tetrahydro - 3 - furanyl]oxy] - 6 - quinazolinyl] - 4 - (dimethylamino) - 2 - butenamide (2Z)-2-butenedioate (1:2)
Molecular Formula: C24H25ClFN5O3•2C4H4O4
CAS Number: 850140-73-7

Introduction

Antineoplastic agent; a second-generation inhibitor of receptor tyrosine kinases.1 7 8

Uses for Gilotrif

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 test1 2 3 5 16 (designated an orphan drug by FDA for this use).4

Safety and efficacy not established in patients with EGFR mutations other than exon 19 deletion or exon 21 substitution.1

Gilotrif 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.1

  • 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).1

Dosage

Available as afatinib dimaleate; dosage expressed in terms of afatinib.1

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.2

Dosage Modification

Dosage reduction, temporary interruption, or permanent discontinuance of therapy may be necessary.1

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.1

Grade 3 or 4 Toxicity

If grade 3 or 4 toxicity occurs, temporarily interrupt afatinib therapy.1 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).1

Diarrhea

If grade 2 diarrhea persists for >48 hours or grade 3 or greater diarrhea occurs, temporarily interrupt afatinib therapy.1 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).1 (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).1

If life-threatening bullous, blistering, or exfoliating lesions occur, permanently discontinue therapy.1 (See Dermatologic Effects under Cautions.)

Nephrotoxicity

If grade 2 or greater nephrotoxicity occurs, temporarily interrupt afatinib 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).1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No adjustment of initial dosage needed.1

Severe hepatic impairment (Child-Pugh class C): Monitor closely and adjust dosage if not tolerated.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild renal impairment (Clcr 60–89 mL/minute): No adjustment of initial dosage needed.1

Moderate or severe renal impairment (Clcr ≤59 mL/minute): Monitor closely and adjust dosage if not tolerated.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Gilotrif

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Diarrhea

Diarrhea resulting in dehydration with or without renal impairment, sometimes fatal, reported.1 In principal efficacy study, diarrhea occurred in 96% and was severe (grade 3) in 15% of patients receiving afatinib.1 2 Diarrhea generally occurred within first 6 weeks of therapy.1

If persistent or severe diarrhea occurs, temporarily interrupt therapy and reduce subsequent dosage.1 (See Diarrhea under Dosage and Administration.)

Provide patients with antidiarrheal therapy (e.g., loperamide) for subsequent home use as needed.1 Advise patients to take antidiarrheal agent at onset of diarrhea and until loose bowel movements have ceased for 12 hours.1

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.1 Grade 1–3 palmar-plantar erythrodysesthesia (hand-foot syndrome) also reported.1

May manage afatinib-associated rash with topical or systemic corticosteroids, anti-infectives, or antihistamines.17

If severe or persistent cutaneous reactions occur, temporarily interrupt therapy and reduce subsequent dosage.1 (See Dermatologic Toxicity under Dosage and Administration.)

Permanently discontinue afatinib in patients who develop life-threatening bullous, blistering, or exfoliating lesions.1

Pulmonary Effects

Interstitial lung disease or interstitial lung disease-like events (e.g., lung infiltration, pneumonitis, ARDS, allergic alveolitis), sometimes fatal, reported.1 2 Incidence of interstitial lung disease reportedly higher in Asian patients compared with non-Asian patients.1

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

Hepatic Toxicity

Abnormal liver function tests, sometimes fatal, reported.1

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

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.1

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.1

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.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryofetal toxicity (e.g., abortion) and teratogenicity demonstrated in animals.1 Pregnancy should be avoided during therapy and for at least 2 weeks after drug discontinuance.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Cardiovascular Effects

Left ventricular dysfunction reported.1 Permanently discontinue afatinib if symptomatic left ventricular dysfunction occurs.1

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).1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.1

Hepatic Impairment

Systemic exposure not affected by mild or moderate hepatic impairment (Child-Pugh class A or B).1

Not studied in patients with severe hepatic impairment (Child-Pugh class C); therefore, monitor closely.1 (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).1 (See Renal Impairment under Dosage and Administration.)

Not studied in patients with severe renal impairment (Clcr <30 mL/minute); monitor closely.1

Common Adverse Effects

Diarrhea,1 2 5 rash/dermatitis acneiform,1 2 5 mucositis or stomatitis,1 2 5 paronychia,1 2 5 dry skin,1 2 decreased appetite,1 2 5 pruritus,1 2 5 epistaxis,1 2 5 weight loss,1 cystitis,1 cheilitis,1 2 pyrexia,1 rhinorrhea,1 conjunctivitis,1 nausea,2 vomiting,2 fatigue,2 5 elevated AST/ALT concentrations,1 5 hypokalemia.1

Interactions for Gilotrif

Does not inhibit or induce CYP isoenzyme 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro.1 CYP-mediated mechanisms play a minor role in overall metabolism.1 9

Substrate and inhibitor of P-glycoprotein (P-gp) and ABCG2 (breast cancer resistance protein [BCRP]) in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP inhibitors or inducers: Clinically important pharmacokinetic interactions unlikely.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP substrates: Clinically important pharmacokinetic interactions unlikely.1

Drugs Affecting the P-glycoprotein Transport System

P-gp inhibitors: Possible pharmacokinetic interaction (increased systemic exposure to afatinib).1 Reduce dosage of afatinib if not tolerated.1 (See Specific Drugs under Interactions.)

P-gp inducers: Possible pharmacokinetic interaction (decreased systemic exposure to afatinib).1 Increase dosage of afatinib as tolerated.1 (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Possible increased systemic exposure to afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If amiodarone (a P-gp inhibitor) is discontinued, resume afatinib at the dosage used prior to initiation of amiodarone as tolerated1

Antifungals, azoles (e.g., itraconazole, ketoconazole)

P-gp inhibitors: Possible increased systemic exposure to afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If the P-gp inhibitor is discontinued, resume afatinib at the dosage used prior to initiation of the P-gp inhibitor as tolerated1

Antiretrovirals, HIV protease inhibitors (e.g., nelfinavir, ritonavir, saquinavir)

P-gp inhibitors: Possible increased systemic exposure to afatinib1

Ritonavir: Afatinib AUC and peak plasma concentration increased by 48 and 39%, respectively, when ritonavir administered 1 hour prior to afatinib; no substantial effect on afatinib AUC when ritonavir administered concomitantly with or 6 hours following afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If the P-gp inhibitor is discontinued, resume afatinib at the dosage used prior to initiation of the P-gp inhibitor as tolerated1

Carbamazepine

Possible decreased systemic exposure to afatinib1

Increase afatinib dosage by 10 mg daily as tolerated1

If carbamazepine (a P-gp inducer) is discontinued, resume afatinib (2–3 days following discontinuance of carbamazepine) at the dosage used prior to initiation of carbamazepine1

Cisplatin

No substantial effect on pharmacokinetics of cisplatin15

Cyclosporine

Possible increased systemic exposure to afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If cyclosporine (a P-gp inhibitor) is discontinued, resume afatinib at the dosage used prior to initiation of cyclosporine as tolerated1

Erythromycin

Possible increased systemic exposure to afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If erythromycin (a P-gp inhibitor) is discontinued, resume afatinib at the dosage used prior to initiation of erythromycin as tolerated1

Fluorouracil

No substantial effect on pharmacokinetics of fluorouracil15

Paclitaxel

No substantial effect on pharmacokinetics of paclitaxel15

Phenobarbital

Possible decreased systemic exposure to afatinib1

Increase afatinib dosage by 10 mg daily as tolerated1

If phenobarbital (a P-gp inducer) is discontinued, resume afatinib (2–3 days following discontinuance of phenobarbital) at the dosage used prior to initiation of phenobarbital1

Phenytoin

Possible decreased systemic exposure to afatinib1

Increase afatinib dosage by 10 mg daily as tolerated1

If phenytoin (a P-gp inducer) is discontinued, resume afatinib (2–3 days following discontinuance of phenytoin) at the dosage used prior to initiation of phenytoin1

Quinidine

Possible increased systemic exposure to afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If quinidine (a P-gp inhibitor) is discontinued, resume afatinib at the dosage used prior to initiation of quinidine1

Rifampin

Afatinib AUC and peak plasma concentration decreased by 34 and 22%, respectively1

Increase afatinib dosage by 10 mg daily as tolerated1

If rifampin (a P-gp inducer) is discontinued, resume afatinib (2–3 days following discontinuance of rifampin) at the dosage used prior to initiation of rifampin 1

St. John's wort (Hypericum perforatum)

Possible decreased systemic exposure to afatinib1

Increase afatinib dosage by 10 mg daily as tolerated1

If St. John's wort (a P-gp inducer) is discontinued, resume afatinib (2–3 days following discontinuance of the herbal supplement) at the dosage used prior to initiation of the herbal supplement1

Tacrolimus

Possible increased systemic exposure to afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If tacrolimus (a P-gp inhibitor) is discontinued, resume afatinib at the dosage used prior to initiation of tacrolimus as tolerated1

Verapamil

Possible increased systemic exposure to afatinib1

Reduce afatinib dosage by 10 mg daily if not tolerated1

If verapamil (a P-gp inhibitor) is discontinued, resume afatinib at the dosage used prior to initiation of verapamil as tolerated1

Gilotrif Pharmacokinetics

Absorption

Bioavailability

Peak plasma afatinib concentrations are attained about 2–5 hours after oral administration.1 7

AUC and peak plasma concentration increase slightly more than dose proportionally over a dosage range of 20–50 mg.1

Steady-state concentrations are achieved within 8 days of repeated administration, resulting in an accumulation of 2.8 fold (for AUC) and 2.1 fold (for peak plasma concentration).1

Food

Administration with a high-fat meal decreased peak plasma concentration and AUC by 50 and 39%, respectively, compared with fasted state.1 (See Administration under Dosage and Administration.)

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B) does not affect exposure to afatinib.1

Median trough afatinib concentrations in patients with mild (Clcr 60–89 mL/minute) or moderate renal impairment (Clcr 30–59 mL/minute) were 27 or 85% higher, respectively, compared with patients with normal renal function.1

Distribution

Extent

Not known whether afatinib is distributed into milk.1

Plasma Protein Binding

Approximately 95%.1

Elimination

Metabolism

CYP-mediated mechanisms have a minor role in overall metabolism.1 9

Elimination Route

Eliminated in feces (85%) and urine (4%), mostly (88%) as unchanged drug.1

Half-life

37 hours.1 7 9

Special Populations

Age, weight, gender, and race do not substantially affect exposure to afatinib.1

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.1

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.1 7 8 9 11

  • 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 gefitinib7 8 9 10 11 ).

  • Inhibits proliferation of cell lines that overexpress HER2 in vitro.1

  • Inhibits tumor growth in mice with tumors overexpressing wild-type EGFR, HER2, or the EGFR L858R/T790M mutation.1

  • 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.9 11

Advice to Patients

  • Importance of advising patients to take afatinib on an empty stomach, at least 1 hour before or 2 hours after a meal.1 If a dose is missed, instruct patients to take the missed dose as soon as it is remembered unless it is within 12 hours of the next scheduled dose, in which case they should not take the missed dose.1 Advise patients to not take 2 doses at the same time to make up for a missed dose.1

  • Risk of diarrhea; importance of advising patient about appropriate countermeasures to manage diarrhea.1 Importance of informing clinician if diarrhea develops and promptly seeking medical attention if severe or persistent diarrhea occurs.1

  • Risk of cutaneous reactions.1 Importance of limiting exposure to sunlight by wearing protective clothing and using sunscreen (minimum SPF of 15).1 17

  • Risk of interstitial lung disease.1 Importance of immediately informing clinician if new or worsening respiratory symptoms occur or if any combination of the following symptoms occur: difficulty breathing, shortness of breath, cough, and/or fever.1

  • Risk of hepatotoxicity and importance of periodic liver function test monitoring.1 Importance of immediately reporting any manifestations of hepatotoxicity (e.g., jaundice, unusually dark or “tea-colored” urine, right upper quadrant pain, fatigue, bleeding or bruising more easily than normal).1

  • Risk of ocular effects.1 Importance of immediately informing clinician if ocular problems (e.g., eye pain, swelling, redness, blurred vision, other vision changes) occur.1

  • Risk of left ventricular dysfunction; importance of immediately informing clinicians if new-onset or worsening shortness of breath, exercise intolerance, cough, fatigue, peripheral edema, palpitations, or sudden weight gain occurs.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use adequate methods of contraception while receiving afatinib and for at least 2 weeks after the drug is discontinued.1 Importance of patients informing their clinicians if they are pregnant or think they may be pregnant.1

  • Importance of advising women to avoid breast-feeding while receiving afatinib therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Afatinib Dimaleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

20 mg (of afatinib)

Gilotrif

Boehringer Ingelheim

30 mg (of afatinib)

Gilotrif

Boehringer Ingelheim

40 mg (of afatinib)

Gilotrif

Boehringer Ingelheim

AHFS DI Essentials. © Copyright 2016, Selected Revisions July 1, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Boehringer Ingelheim Pharmaceuticals, Inc. Gilotrif (afatinib) tablets prescribing information. Ridgefield, CT; 2013 Nov.

2. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31:3327-34. [PubMed 23816960]

3. Yang JC, Hirsh V, Schuler M et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31:3342-50. [PubMed 23816967]

4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Feb 25.

5. Wu YL, Zhou C, Hu CP et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15:213-22. [PubMed 24439929]

6. Wind S, Giessmann T, Jungnik A et al. Pharmacokinetic drug interactions of afatinib with rifampicin and ritonavir. Clin Drug Investig. 2014; 34:173-82. [PubMed 24399452]

7. Murakami H, Tamura T, Takahashi T et al. Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4). Cancer Chemother Pharmacol. 2012; 69:891-9. [PubMed 22071596]

8. Ou SH. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. Crit Rev Oncol Hematol. 2012; 83:407-21. [PubMed 22257651]

9. Nelson V, Ziehr J, Agulnik M et al. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther. 2013; 6:135-43. [PubMed 23493883]

10. Köhler J, Schuler M. Afatinib, erlotinib and gefitinib in the first-line therapy of EGFR mutation-positive lung adenocarcinoma: a review. Onkologie. 2013; 36:510-8. [PubMed 24051929]

11. Li D, Ambrogio L, Shimamura T et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008; 27:4702-11. [PubMed 18408761]

12. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 201292Orig1s000: Summary review. From FDA website.

15. Vermorken JB, Rottey S, Ehrnrooth E et al. A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors. Ann Oncol. 2013; 24:1392-400. [PubMed 23293114]

16. Yang JC, Shih JY, Su WC et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012; 13:539-48. [PubMed 22452895]

17. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 201292Orig1s000: Medical review(s). From FDA website.

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