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  • CLASSES

    Small Molecule Antineoplastic EGFR (HER1) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral tyrosine-kinase inhibitor
    Used for certain types of metastatic non-small cell lung cancer
    Withhold afatinib for severe or prolonged diarrhea not responsive to anti-diarrheal agents

    COMMON BRAND NAMES

    GILOTRIF

    HOW SUPPLIED

    GILOTRIF Oral Tab: 20mg, 30mg, 40mg

    DOSAGE & INDICATIONS

    For the treatment of patients with metastatic non-small cell lung cancer (NSCLC).
    For the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test.
    Oral dosage
    Adults

    40 mg orally once daily until disease progression or unacceptable toxicity; afatinib should be taken on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Afatinib monotherapy (n = 230) was compared with pemetrexed and cisplatin combination therapy (n = 115) in a randomized, multicenter, open label phase III trial of patients with EGFR positive, metastatic NSCLC. The primary endpoint of progression-free survival (PFS) was significantly improved in patients treated with afatinib compared with chemotherapy (11.1 months vs. 6.9 months); overall response rate was also improved (50.4% vs. 19.1%). There was no statistically significant difference in overall survival at the final pre-planned analysis (28.2 vs. 28.2 months). A preplanned exploratory subgroup analysis found that patients with EGFR exon 19 deletions responded to afatinib therapy better that those with exon 12 (L858R) substitution mutations or a combination of exon 19 deletions and exon 12 (L858R) substitutions (PFS: HR, 0.28 vs. 0.73 vs. 0.47; OS: HR, 0.55 vs. 1.3 vs. 0.82). Afatinib was also effective in a pooled analysis of NSCLC patients with non-resistant EGFR mutations other than exon 19 deletions or exon 21 L858R substitutions (S768I, L861Q, and G719X) (n = 32).

    For the treatment of metastatic squamous NSCLC, progressing after platinum-based chemotherapy.
    Oral dosage
    Adults

    40 mg orally once daily until disease progression or unacceptable toxicity; afatinib should be taken on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with platinum-resistant metastatic squamous NSCLC were treated with either afatinib (n = 398) or erlotinib (n = 397) until disease progression in a randomized, multicenter, open-label clinical trial. Patients treated with afatinib experienced significant improvements in the primary outcome of progression-free survival (PFS) by independent review committee (IRC) compared with erlotinib (2.4 months vs. 1.9 months), as well as in overall survival (OS) (7.9 months vs. 6.8 months). The overall response rate (ORR) by IRC was 3% (95% CI, 1.7% to 5.8%) for patients treated with afatinib compared with 2% (95% CI, 0.8% to 4.3%) for those who received erlotinib.

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO; 50 mg/day PO if taking a P-glycoprotein inducer.

    Geriatric

    40 mg/day PO; 50 mg/day PO if taking a P-glycoprotein inducer.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment: 
    Mild to moderate hepatic impairment (Child-Pugh class A or B): No adjustment to the starting dose is needed to.
    Severe hepatic impairment (Child-Pugh class C): Afatinib has not been studied in these patients, however it is not extensively metabolized in the liver. Closely monitor these patients and adjust the dose if not tolerated.
    Treatment-Related Hepatotoxicity: 
    Hold afatinib therapy in patients who develop worsening liver function. When toxicity resolves to grade 1 or less, resume therapy at a reduced dose (i.e., 10 mg/day less than the dose causing hepatotoxicity). Permanently discontinue therapy for severe drug-induced hepatic impairment or if hepatotoxicity persists at a dose of 20 mg/day.

    Renal Impairment

    Baseline Renal Impairment:
    Mild to moderate renal impairment (CrCL 30 mL/min or more): No adjustment to the starting dose is needed. Closely monitor patients and adjust the afatinib dose if not tolerated.
    Severe renal impairment (CrCL 15 to 29 mL/min as calculated by the Modificaiton of Diet in Renal Disease (MDRD) formula): Reduce the starting dose of afatinib to 30 mg once daily.
    CrCL less than 15 mL/min or dialysis: Afatinib has not been studied in this population; recommendations for dosing cannot be made..
     
    Treatment-Related Nephrotoxicity:
    Grade 2 or higher (SCr greater than 1.5 times upper limit of normal (ULN)): Hold afatinib therapy until the toxicity resolves to grade 1 or less (SCr less than 1.5 x ULN), then resume therapy at a reduced dose (i.e., 10 mg/day less than the dose causing nephrotoxicity). Permanently discontinue therapy if nephrotoxicity persists at a dose of 20 mg/day.

    ADMINISTRATION

    Oral Administration

    NOTE: Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
     
    Afatinib must be given orally on an empty stomach, 1 hour before or 2 hours after the ingestion of food. Administer at the same time each day. Do not administer with food.
    Do not administer a missed dose within 12 hours of the next dose.

    STORAGE

    GILOTRIF:
    - Avoid excessive humidity
    - Protect from light
    - Store and dispense in original container
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Asian patients, pneumonitis, pulmonary disease, respiratory distress syndrome

    Interstitial pulmonary disease and interstitial lung disease-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or allergic alveolitis) have been associated with the use of afatinib. The incidence appears to be higher in Asian patients (2.3%) compared to Caucasians (1%). In the event of acute onset of new or progressive, unexplained pulmonary symptoms or respiratory insufficiency such as dyspnea, cough, and fever, afatinib therapy should be interrupted pending diagnostic evaluation. If interstitial lung disease is diagnosed, afatinib should be discontinued and appropriate treatment instituted as necessary.

    Dehydration, diarrhea, renal failure, renal impairment

    Diarrhea, which can result in dehydration and renal failure or renal impairment, has been associated with the use of afatinib in the majority of patients; some of these cases were fatal. Periodically monitor renal function and serum electrolytes in patients at risk of dehydration. Patients should be instructed to take an anti-diarrheal agent (e.g., loperamide) at the onset of diarrhea, and to continue therapy until 12 hours after the last loose stool. Interrupt afatinib for grade 2 diarrhea lasting more than 48 hours, or any grade 3 and higher diarrhea. Therapy may be resumed with the appropriate dose reduction when diarrhea resolves to grade 1 or less.

    Contact lenses, inflammation, keratitis, ocular disease, visual disturbance

    Afatinib may cause symptoms consistent with ocular disease. Patients who develop an onset of new eye symptoms or visual disturbance such as ocular pain, inflammation, lacrimation, light sensitivity, blurred vision, and/or red eye should be evaluated and managed appropriately. Interrupt afatinib if patients present with acute or worsening ocular pain or suspected keratitis. If keratitis is diagnosed, consider the risks and benefits of continuing treatment; a continued interruption or discontinuation of therapy is necessary if ulcerative keratitis is diagnosed. Ocular disorders such as abnormal eyelash growth, keratoconjunctivitis, and keratitis are known risk factors for corneal perforation and ulceration; the use of contact lenses is also a risk factor. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye.

    Serious rash, skin disease

    Serious rash and skin disease, including bullous, blistering, and exfoliating lesions, has been reported with the use of afatinib, in addition to post-marketing cases consistent with toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS); more common cutaneous toxicities including acneiform rash, erythema, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) have also been reported. Discontinue afatinib in patients who develop life-threatening bullous, blistering, or exfoliating lesions, or if TEN or SJS is suspected. For patients who develop prolonged grade 2 cutaneous adverse reactions, or if skin reactions are intolerable, hold afatinib therapy until resolution to grade 1 or less and resume therapy with an appropriate dose reduction.

    Breast cancer

    Patients with HER2-positive metastatic breast cancer treated with afatinib in combination with vinorelbine had decreased overall survival compared with patients who received vinorelbine in combination with trastuzumab at an interim analysis of a randomized, controlled, phase III clinical trial (LUX-Breast 1). Additionally, adverse reactions including diarrhea, rash, infection (with fatalities), and progressive disease occurred more frequently in the afatinib group. Another randomized, open-label, phase II clinical trial of patients with HER2-positive breast cancer and brain metastases (LUX-Breast 3) failed to show benefit of afatinib monotherapy or afatinib in combination with vinorelbine over other treatments (investigator's choice) in the primary endpoint of patient benefit at 12 weeks, or secondary endpoints of progression-free survival or overall survival.

    Hepatic disease, hepatotoxicity

    Hepatotoxicity has occurred in patients treated with afatinib; some cases have been fatal. Periodically monitor liver function tests. Hold afatinib therapy in patients who develop worsening liver function, and discontinue treatment if severe hepatic impairment occurs. Use afatinib with caution in patients with pre-existing hepatic disease.

    Pregnancy

    Although there are no adequate studies in pregnant women using afatinib, based on findings for animal studies and its mechanism of action, afatinib may cause fetal harm when administered during pregnancy. Pregnancy should be avoided during treatment and for at least 2 weeks after the last dose of afatinib. If afatinib is used during pregnancy or if a patient becomes pregnant while receiving this drug, she should be apprised of the potential harm to the fetus or the potential for the loss of the pregnancy. Administration of afatinib to pregnant rabbits during organogenesis at exposures approximately 0.2 times or more the exposure by AUC at the recommended human dose of 40 mg resulted in increased post-implantation loss; in animals showing maternal toxicity, abortion at late gestational stages occurred. At higher exposures (0.7 times the exposure by AUC at the recommended human dose), there were decreased fetal weights, increased incidence of runts, as well as visceral and dermal variations. Skeletal alterations (including incomplete or delayed ossifications) and reduced fetal weight occurred in an embryo-fetal development study in rats exposed to afatinib at approximately twice the exposure based on AUC at the recommended human dose.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during afatinib treatment. Afatinib can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 2 weeks after treatment with afatinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of afatinib. Women who become pregnant while receiving afatinib should be apprised of the potential hazard to the fetus. In addition, based on animal data, afatinib treatment may result in impaired fertility or infertility in both females and males of reproductive potential; it is unknown if these effects are reversible.

    Breast-feeding

    It is not known if afatinib is excreted in human breast milk. Due to the potential for serious adverse reactions in the nursing infant, women should avoid breast-feeding during treatment and for 2 weeks after the last dose.

    ADVERSE REACTIONS

    Severe

    diarrhea / Early / 11.0-16.0
    acneiform rash / Delayed / 7.0-16.0
    stomatitis / Delayed / 4.0-9.4
    hypokalemia / Delayed / 1.0-8.0
    nausea / Early / 2.0-4.0
    vomiting / Early / 1.0-4.0
    elevated hepatic enzymes / Delayed / 0.2-3.5
    heart failure / Delayed / 0-2.2
    renal failure (unspecified) / Delayed / 1.3-2.0
    weight loss / Delayed / 0-1.0
    acute respiratory distress syndrome (ARDS) / Early / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    leukopenia / Delayed / 0.4-1.0
    pancreatitis / Delayed / 0-1.0
    keratitis / Delayed / 0-0.5
    xerosis / Delayed / 0-0.4
    neutropenia / Delayed / 0-0.4
    anemia / Delayed / 0-0.4
    hepatic failure / Delayed / 0-0.2
    bullous rash / Early / 0.2
    pruritus / Rapid / 0.4
    cystitis / Delayed / 1.0
    infection / Delayed / 11.0
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known

    Moderate

    pneumonitis / Delayed / 1.0-10.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 1.5-7.0
    constipation / Delayed / 0-2.6
    conjunctivitis / Delayed / 11.0
    dehydration / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    ocular inflammation / Early / Incidence not known
    dyspnea / Early / Incidence not known

    Mild

    cheilitis / Delayed / 0-12.0
    epistaxis / Delayed / 17.0
    rhinorrhea / Early / 11.0
    fatigue / Early / 1.7
    acne vulgaris / Delayed / Incidence not known
    rash / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    lacrimation / Early / Incidence not known
    ocular pain / Early / Incidence not known
    fever / Early / Incidence not known
    cough / Delayed / Incidence not known

    DRUG INTERACTIONS

    Amiodarone: (Moderate) If the concomitant use of amiodarone and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of amiodarone. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) If the concomitant use of clarithromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of clarithromycin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) If the concomitant use of clarithromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of clarithromycin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Apalutamide: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with apalutamide is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of apalutamide. Afatinib is a P-glycoprotein (P-gp) substrate and apalutamide is a weak P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Atazanavir; Cobicistat: (Moderate) If the concomitant use of cobicistat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cobicistat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with phenobarbital is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of phenobarbital. Afatinib is a P-glycoprotein (P-gp) substrate and phenobarbital is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with phenobarbital is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of phenobarbital. Afatinib is a P-glycoprotein (P-gp) substrate and phenobarbital is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Brigatinib: (Moderate) If the concomitant use of brigatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of brigatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Cabozantinib: (Moderate) If the concomitant use of cabozantinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cabozantinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Carbamazepine: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with carbamazepine is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of carbamazepine. Afatinib is a P-glycoprotein (P-gp) substrate and carbamazepine is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Carvedilol: (Moderate) If the concomitant use of carvedilol and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of carvedilol. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and carvedilol is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Clarithromycin: (Moderate) If the concomitant use of clarithromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of clarithromycin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Cobicistat: (Moderate) If the concomitant use of cobicistat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cobicistat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) If the concomitant use of cobicistat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cobicistat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) If the concomitant use of cobicistat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cobicistat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Conivaptan: (Moderate) If the concomitant use of conivaptan and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of conivaptan. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and conivaptan is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Cyclosporine: (Moderate) If the concomitant use of cyclosporine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cyclosporine. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Daclatasvir: (Moderate) If the concomitant use of daclatasvir and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of daclatasvir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and daclatasvir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. The ratio of digoxin Cmax, AUC, and Cmin when administered with daclatasvir (60 mg daily) or alone was 1.65, 1.27, and 1.18, respectively. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Darunavir; Cobicistat: (Moderate) If the concomitant use of cobicistat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cobicistat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) If the concomitant use of cobicistat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cobicistat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) If the concomitant use of paritaprevir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of paritaprevir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and paritaprevir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib. (Moderate) If the concomitant use of ritonavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ritonavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Dextromethorphan; Quinidine: (Moderate) If the concomitant use of quinidine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of quinidine. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Dronedarone: (Moderate) If the concomitant use of dronedarone and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of dronedarone. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Eliglustat: (Moderate) If the concomitant use of eliglustat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of eliglustat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and eliglustat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Erythromycin: (Moderate) If the concomitant use of erythromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of erythromycin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Erythromycin; Sulfisoxazole: (Moderate) If the concomitant use of erythromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of erythromycin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Etravirine: (Moderate) If the concomitant use of etravirine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of etravirine. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and etravirine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Flibanserin: (Moderate) If the concomitant use of flibanserin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of flibanserin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and flibanserin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Fosamprenavir: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with fosamprenavir is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of fosamprenavir. Afatinib is a P-glycoprotein (P-gp) substrate and fosamprenavir is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Fosphenytoin: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with fosphenytoin is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of fosphenytoin. Afatinib is a P-glycoprotein (P-gp) substrate and fosphenytoin is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Fostamatinib: (Moderate) If the concomitant use of fostamatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of fostamatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and fostamatinib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Glecaprevir; Pibrentasvir: (Moderate) If the concomitant use of glecaprevir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of glecaprevir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and glecaprevir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib. (Moderate) If the concomitant use of pibrentasvir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of pibrentasvir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and pibrentasvir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Grapefruit juice: (Major) Due to the potential for increased afatinib exposure, patients should be advised to avoid intake of grapefruit or grapefruit juice during afatinib therapy. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and grapefruit juice is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when the Pgp inhibitor was administered at the same time as afatinib or 6 hours later. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at an afatinib dose of 20 mg per day, but does not address a minimum dose otherwise.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with rifampin is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of rifampin. Afatinib is a P-glycoprotein (P-gp) substrate and rifampin is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with rifampin decreased afatinib exposure by 34%.
    Isoniazid, INH; Rifampin: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with rifampin is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of rifampin. Afatinib is a P-glycoprotein (P-gp) substrate and rifampin is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with rifampin decreased afatinib exposure by 34%.
    Itraconazole: (Moderate) If the concomitant use of itraconazole and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of itraconazole. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and itraconazole is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Ivacaftor: (Moderate) If the concomitant use of ivacaftor and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ivacaftor. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. Ivacaftor and its M1 metabolite are weak P-gp inhibitors; coadministration may increase plasma concentrations of afatinib. Coadministration of ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Ketoconazole: (Moderate) If the concomitant use of ketoconazole and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ketoconazole. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ketoconazole is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Lapatinib: (Moderate) If the concomitant use of lapatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of lapatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Ledipasvir; Sofosbuvir: (Moderate) If the concomitant use of ledipasvir; sofosbuvir and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ledipasvir; sofosbuvir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and ledipasvir is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Lomitapide: (Moderate) If the concomitant use of lomitapide and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of lomitapide. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and lomitapide is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Lopinavir; Ritonavir: (Moderate) If the concomitant use of lopinavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of lopinavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and lopinavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib. (Moderate) If the concomitant use of ritonavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ritonavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of afatinib with lumacaftor; ivacaftor if possible, due to unpredictability of clinical effect. Although the clinical significance of this interaction is unknown, concurrent use of afatinib and lumacaftor; ivacaftor may alter afatinib exposure; caution and close monitoring are advised if these drugs are used together. Afatinib is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to either decreased efficacy of afatinib or increased or prolonged therapeutic effects and adverse events. FDA-approved labeling for afatinib recommends reducing the dose by 10 mg per day if the original dose is not tolerated when administered with P-gp inhibitors, and increasing the dose by 10 mg/day as tolerated when given with P-gp inducers. Administration of the P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. Pre-treatment with a strong P-gp inducer, rifampicin (600 mg daily for 7 days), decreased the afatinib AUC by 34% and the Cmax by 22%.
    Lumacaftor; Ivacaftor: (Moderate) If the concomitant use of ivacaftor and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ivacaftor. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. Ivacaftor and its M1 metabolite are weak P-gp inhibitors; coadministration may increase plasma concentrations of afatinib. Coadministration of ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Mefloquine: (Moderate) If the concomitant use of mefloquine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of mefloquine. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and mefloquine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Mephobarbital: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with mephobarbital is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of mephobarbital. Afatinib is a P-glycoprotein (P-gp) substrate and mephobarbital is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Mifepristone: (Moderate) If the concomitant use of mifepristone and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of mifepristone. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and mifepristone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Nelfinavir: (Moderate) If the concomitant use of nelfinavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of nelfinavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and nelfinavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Neratinib: (Moderate) If the concomitant use of neratinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of neratinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) If the concomitant use of paritaprevir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of paritaprevir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and paritaprevir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib. (Moderate) If the concomitant use of ritonavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ritonavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Osimertinib: (Moderate) If the concomitant use of osimertinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of osimertinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate. Osimertinib inhibits P-gp. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenobarbital: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with phenobarbital is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of phenobarbital. Afatinib is a P-glycoprotein (P-gp) substrate and phenobarbital is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Phenytoin: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with phenytoin is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of phenytoin. Afatinib is a P-glycoprotein (P-gp) substrate and phenytoin is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Ponatinib: (Moderate) If the concomitant use of ponatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ponatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ponatinib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Posaconazole: (Moderate) If the concomitant use of posaconazole and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of posaconazole. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and posaconazole is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Primidone: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with primidone is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of primidone. Afatinib is a P-glycoprotein (P-gp) substrate and primidone is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Propafenone: (Moderate) If the concomitant use of propafenone and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of propafenone. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Quinidine: (Moderate) If the concomitant use of quinidine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of quinidine. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Ranolazine: (Moderate) If the concomitant use of ranolazine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ranolazine. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ranolazine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Rifampin: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with rifampin is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of rifampin. Afatinib is a P-glycoprotein (P-gp) substrate and rifampin is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with rifampin decreased afatinib exposure by 34%.
    Ritonavir: (Moderate) If the concomitant use of ritonavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ritonavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Rolapitant: (Moderate) If the concomitant use of rolapitant and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of rolapitant. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and rolapitant is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Sapropterin: (Moderate) If the concomitant use of sapropterin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of sapropterin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and sapropterin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Saquinavir: (Moderate) If the concomitant use of saquinavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of saquinavir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and saquinavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Sarecycline: (Moderate) If the concomitant use of sarecycline and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of sarecycline. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate; sarecycline is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Simeprevir: (Moderate) If the concomitant use of simeprevir and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of simeprevir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and simeprevir is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Coadministration with simeprevir (150 mg daily for 7 days) increased the Cmax and AUC of another P-gp substrate, digoxin (single dose, 0.5 mg), by 1.31 and 1.39, respectively. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Sofosbuvir; Velpatasvir: (Moderate) If the concomitant use of velpatasvir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of velpatasvir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) If the concomitant use of velpatasvir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of velpatasvir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib. (Moderate) If the concomitant use of voxilaprevir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of voxilaprevir. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and voxilaprevir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Sorafenib: (Moderate) If the concomitant use of sorafenib and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of sorafenib. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and sorafenib is a weak in vitro P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    St. John's Wort, Hypericum perforatum: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with St. Johns Wort is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of St. Johns Wort. Afatinib is a P-glycoprotein (P-gp) substrate and St. Johns Wort is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Tacrolimus: (Moderate) If the concomitant use of tacrolimus and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of tacrolimus. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. While data is conflicting, tacrolimus may be a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Tedizolid: (Moderate) If possible, stop use of afatinib temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for afatinib-associated adverse events. Afatinib plasma concentrations may be increased when administered concurrently with oral tedizolid. Afatinib is an in vitro substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Telaprevir: (Moderate) Concomitant use of afatinib, a P-glycoprotein (P-gp) substrate, and telaprevir, a P-gp inhibitor, may increase the exposure of afatinib. If the use of both agents is necessary, consider reducing the starting afatinib dose to 30 mg/day if the original dose is not tolerated. Resume the previous dose if telaprevir is discontinued.
    Temsirolimus: (Moderate) If the concomitant use of temsirolimus and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of temsirolimus. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Tezacaftor; Ivacaftor: (Moderate) If the concomitant use of ivacaftor and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ivacaftor. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. Ivacaftor and its M1 metabolite are weak P-gp inhibitors; coadministration may increase plasma concentrations of afatinib. Coadministration of ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Tipranavir: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with tipranavir (boosted with ritonavir) is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of tipranavir/ritonavir). Afatinib is a P-glycoprotein (P-gp) substrate. When administered with ritonavir, P-gp is inhibited with the first dose of tipranavir followed by strong induction over time; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Trandolapril; Verapamil: (Moderate) If the concomitant use of verapamil and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of verapamil. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Vemurafenib: (Moderate) If the concomitant use of vemurafenib and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of vemurafenib. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and vemurafenib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Coadministration of vemurafenib (960 mg twice daily for 22 days) with digoxin (single dose, 0.25 mg), a sensitive P-gp substrate, to 22 cancer patients increased the digoxin AUC and Cmax by 1.8-fold and 1.5-fold, respectively. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Venetoclax: (Moderate) If the concomitant use of venetoclax and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of venetoclax. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and venetoclax is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Verapamil: (Moderate) If the concomitant use of verapamil and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of verapamil. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Zonisamide: (Moderate) If the concomitant use of zonisamide and afatinib is necessary, monitor for afatinib-related adverse reactions, especially when starting or stopping zonisamide or changing the zonisamide dose. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of zonisamide. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate studies in pregnant women using afatinib, based on findings for animal studies and its mechanism of action, afatinib may cause fetal harm when administered during pregnancy. Pregnancy should be avoided during treatment and for at least 2 weeks after the last dose of afatinib. If afatinib is used during pregnancy or if a patient becomes pregnant while receiving this drug, she should be apprised of the potential harm to the fetus or the potential for the loss of the pregnancy. Administration of afatinib to pregnant rabbits during organogenesis at exposures approximately 0.2 times or more the exposure by AUC at the recommended human dose of 40 mg resulted in increased post-implantation loss; in animals showing maternal toxicity, abortion at late gestational stages occurred. At higher exposures (0.7 times the exposure by AUC at the recommended human dose), there were decreased fetal weights, increased incidence of runts, as well as visceral and dermal variations. Skeletal alterations (including incomplete or delayed ossifications) and reduced fetal weight occurred in an embryo-fetal development study in rats exposed to afatinib at approximately twice the exposure based on AUC at the recommended human dose.

    It is not known if afatinib is excreted in human breast milk. Due to the potential for serious adverse reactions in the nursing infant, women should avoid breast-feeding during treatment and for 2 weeks after the last dose.

    MECHANISM OF ACTION

    Afatinib is a 4-anilinoquinazoline tyrosine kinase inhibitor that irreversibly inhibits tyrosine kinase autophosphorylation by covalently binding to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4). This results in blockage of downstream EGFR signal transduction pathways, cell cycle arrest, and inhibition of angiogenesis.
     
    Ligand binding (e.g., EGF, PDGF) activates receptor tyrosine kinases, causing phosphorylation of tyrosine residue in different substrates and leading to cell proliferation, differentiation, migration, metabolism, and apoptosis. Certain EGFR mutations, including non-resistant mutations in its kinase domain, can result in autophosphorylation of the receptor, leading to receptor activation (sometimes in the absence of ligand binding). Non-resistant mutations are those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation, the most common of which are exon 21 L858R substitutions and exon 19 deletions. Afatinib inhibited autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at concentrations achieved in patients; it also inhibited in vitro proliferation of cell lines overexpressing HER2.

    PHARMACOKINETICS

    Afatinib is administered orally, and is approximately 95% bound to plasma proteins. Total body clearance after a dose of 40 mg at steady state is 1,070 mL/min and volume of distribution is 2,870 L. Time to reach steady state is approximately 8 days. The elimination half-life is approximately 37 hours. Afatinib is primarily excreted as unchanged drug via the feces (85%), with renal elimination accounting for 4%. Only 12% of the recovered dose is present as metabolites.
     
    Affected cytochrome P450 isoenzymes and drug transporters: P-glylcoprotein (P-gp)
    Afatinib undergoes minimal enzymatic metabolism, mainly via Michael adduct formation to proteins and nucleophilic small molecules. Approximately 9% of the total metabolic turnover is a result of CYP450-dependent reactions, and 2% of the dose is metabolized by flavin containing monooxygenase 3 (FMO3). Based on in vitro data, afatinib is both a substrate and an inhibitor of P-glycoprotein; concomitant use with inhibitors or inducers of P-gp may affect exposure to afatinib.

    Oral Route

    Afatinib is slowly absorbed, with peak plasma levels occurring 2 to 5 hours after dosing. Relative bioavailability after tablet administration compared to an oral solution is 92%. Afatinib exposure increases in a non-linear, greater than dose-proportional manner. Over a range of 20 to 50 mg, the mean AUC at steady state is 380 to 1,130 ng x hours/mL and Cmax 24.5 to 77 ng/mL. When given with a high-fat meal, Cmax decreases by 50%, and AUC decreases by 39%. Afatinib should be given on an empty stomach due to the potential for decreased efficacy resulting from the decrease in exposure.