Gefitinib is an oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). EGRF is expressed, overexpressed, or dysregulated in many cancers including breast, ovarian, non-small cell (NSCLC), mesothelioma, colorectal, and head and neck cancers. Clinically, EGFR expression has been associated with poor prognosis, development of metastasis, and resistance to chemotherapy, hormonal therapy, and radiation therapy. Gefitinib was originally approved by the FDA in 2002 for the third-line treatment of advanced NSCLC. However, in 2005 the indication was modified to only include patients who benefited from either current or past gefitinib treatment, due to a large clinical trial in patients with refractory NSCLC showing no survival benefit, as well as the early termination of another clinical trial after an interim analysis due to a lack of survival at in advanced NSCLC following chemotherapy and radiation. Of note, the impact of EGFR status on efficacy was unknown at that time. In 2015, the FDA approved gefitinib for the first-line treatment of metastatic NSCLC in patients with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations based on a small, single-arm, open-label study. Serious adverse reactions include interstitial lung disease, liver damage, gastrointestinal perforation, severe diarrhea, bullous and exfoliative skin disorders, and ocular disorders; the most common side effects are diarrhea and skin reactions. Periodically monitor liver function tests during therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
Pediatrics:
-Doses 150 to 500 mg/m2/day: Low
Adults:
-Minimal/Low
Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
-Gefitinib is given orally with or without food.
-For patients who have difficulty swallowing, drop a gefitinib tablet into 4 to 8 ounces of water. Do not crush the tablet. Stir until it is dispersed (approximately 15 minutes) and drink the liquid immediately. Rinse the glass with 4 to 8 ounces of water and immediately drink. The liquid can also be administered through a naso-gastric (NG) tube.
-Do not take a missed dose within 12 hours of the next dose.
Interstitial lung disease (ILD) or ILD-like reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome (ARDS), or pulmonary fibrosis) have been associated with the use of gefitinib with an overall incidence of 1.3% (grade 3 or higher, 0.7%) across clinical trials, including 3 fatalities. An exploratory exposure-response analysis showed an increase in the incidence of ILD with more than a 2-fold increase in gefitinib exposure. Fatal pneumonia occurred in 0.8% and fatal respiratory failure in 0.9% of patients treated with gefitinib in a multicenter, randomized, double-blind, placebo-controlled clinical trial (n = 1,126), and fever was reported in 9% of patients across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462). Interrupt therapy in patients who develop acute onset or worsening of pulmonary symptoms (e.g., dyspnea, cough, fever); discontinue therapy if ILD is confirmed.
Hepatotoxicity has been reported in patients treated with gefitinib, including fatalities in 0.04% of patients. Elevated hepatic enzymes, including increased ALT (all grade, 11.4%; grade 3 or higher, 5.1%), increased AST (all grade, 7.9%; grade 3 or higher, 3%), and hyperbilirubinemia (all grade, 2.7%; grade 3 or higher, 0.7%) were reported in patients who received gefitinib across clinical trials. Increased transaminases were reported more frequently in a multicenter, randomized, double-blind clinical trial comparing gefitinib with placebo in patients receiving second- or third-line therapy for NSCLC, including increased ALT (all grade, 38% vs. 23%; grade 3 or 4, 2.4% vs. 1.4%) and increased AST (all grade, 40% vs. 25%; grade 3 or 4, 2% vs. 1.3%). Periodically monitor liver function tests; an interruption or discontinuation of therapy may be necessary.
Ocular disorders or visual impairment including conjunctivitis, blepharitis, and xerophthalmia (6.7%); corneal erosion and aberrant eyelash growth (0.2%); and keratitis (0.1%) have been reported across clinical trials in patients treated with gefitinib (n = 2,462); grade 3 ocular disorders occurred in 0.1% of patients. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, the grouped term of conjunctivitis/blepharitis/dry eye (including conjunctival hyperemia, ocular inflammation, ocular irritation, ocular pruritus, eyelid edema, eyelid irritation, and eyelid pruritus) occurred in 6% of patients treated with gefitinib (n = 1,126) compared with 3.2% of those who received placebo (n = 562); all events were grade 1 or 2. Interrupt or discontinue gefitinib for severe or worsening ocular disorders.
Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported with gefitinib therapy; erythema multiforme and dermatitis bullous occurred in 2 patients (0.08%) across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462); palmar-plantar erythrodysesthesia (hand and foot syndrome) occurred in 0.2% of patients. An interruption or discontinuation of treatment is necessary for severe bullous rash or blistering, exfoliating conditions. Additionally, skin reactions (including acne vulgaris, acneiform rash, pustular acne, exfoliative dermatitis, drug eruption, xeroderma, xerosis, erythema, folliculitis, pruritus, rash, macular rash, maculopapular rash, pustular rash, vesicular rash) occurred in 47% (grade 3 or 4, 2%) of gefitinib-treated patients (n = 1,126) compared with 17% (grade 3 or 4, 0.4%) of those who received placebo (n = 562) in a multicenter, randomized, double-blind, placebo-controlled clinical trial of patients receiving 2nd or 3rd line treatment for metastatic NSCLC. Nail disorders, including ingrown nails, nailbed infections, onychoclasis, onycholysis, and paronychia were also reported in 5% (grade 3 or 4, 0.1%) of gefitinib-treated patients compared with 0.7% (grade 3 or 4, 0%) of those treated with placebo; cutaneous vasculitis was also reported in postmarketing experience with gefitinib.
Diarrhea occurred in 29% (grade 3 or 4, 3%) of patients receiving first-line treatment for metastatic NSCLC with gefitinib (n = 1,126) compared with 10% (grade 3 or 4, 1%) of patients who received placebo (n = 562) in a multicenter, randomized, double-blind clinical trial. Monitor patients for diarrhea, as an interruption or discontinuation of therapy may be necessary. Additional gastrointestinal adverse reactions in this trial included anorexia (all grade, 17% vs. 14%; grade 3 or 4, 2.3% vs. 2%), vomiting (all grade, 14% vs. 10%; grade 3 or 4, 1.2% vs. 0.4%), and stomatitis (including cheilitis, glossodynia, oral ulceration, oral inflammation, oral blistering, tongue disorder, and tongue ulceration) (all grade, 7% vs. 4%; grade 3 or 4, 0.3% vs. 0.2%). Nausea (18%), xerostomia (2%), and dehydration (1.8%) were additionally reported across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462); gastrointestinal perforation occurred in 0.1% of patients in these trials. Permanently discontinue gefitinib in patients who develop GI perforation.
Asthenia was reported in 17% of patients treated with gefitinib across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462).
Bleeding, including epistaxis and hematuria, was reported in 4.3% of patients treated with gefitinib across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462); hemorrhagic cystitis has been reported during postmarketing experience with gefitinib. Elevations in international normalized ratio (INR) have also been noted in patients concomitantly taking warfarin; monitor INR and watch for bleeding in patients taking both gefitinib and warfarin.
Pancreatitis has been reported in 0.1% of patients treated with gefitinib across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462).
Allergic reactions, including angioedema and urticaria, occurred in 1.1% of patients treated with gefitinib across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462).
Alopecia was reported in 4.7% of patients treated with gefitinib across non-small cell lung cancer (NSCLC) clinical trials (n = 2,462).
In a multicenter, randomized, double-blind, placebo-controlled clinical trial of patients receiving 2nd or 3rd line therapy for metastatic non-small cell lung cancer (NSCLC), proteinuria occurred in 35% of patients treated with gefitinib (grade 3 or 4, 4.7%) (n = 1,126) compared with 31% of those who received placebo (grade 3 or 4, 3.3%) (n = 562). Elevated serum creatinine also occurred in 1.5% of gefitinib-treated patients across NSCLC clinical trials (n = 2,462), while cystitis was reported in postmarketing experience with gefitinib.
In a multicenter, randomized, double-blind, placebo-controlled clinical trial of patients receiving 2nd or 3rd line therapy for metastatic non-small cell lung cancer (NSCLC), fatal pulmonary embolism was reported in 0.5% of gefitinib-treated patients (n = 1,126).
Use gefitinib with caution in patients with a history of pulmonary disease or chronic lung disease (CLD). Interstitial lung disease (ILD) or ILD-like reactions including lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis have occurred in patients treated with gefitinib across clinical trials, including 3 fatalities. Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease were excluded from non-small cell lung cancer (NSCLC) clinical trials. An exploratory exposure response analysis showed an increase in the incidence of ILD with more than a 2-fold increase in gefitinib exposure. Hold gefitinib therapy in patients who develop acute or worsening pulmonary symptoms such as dyspnea, cough, and fever. Permanently discontinue therapy in patients with confirmed ILD.
Hepatotoxicity has been reported across clinical trials in patients treated with gefitinib, including fatal hepatotoxicity in 0.04%. Use gefitinib with caution in patients with baseline hepatic disease. Obtain periodic liver function tests. Gefitinib should be held for worsening liver function, and discontinued in patients with severe hepatic impairment.
Ocular disorders including keratitis, corneal erosion, aberrant eyelash growth, conjunctivitis, blepharitis, and dry eye have been reported in patients receiving gefitinib treatment. Abnormal eyelash growth and keratitis are known risk factors for corneal perforation and ulceration. Use caution in patients with pre-existing ocular disease. Evaluate and manage any new or worsening vision impairment, eye pain, or other ocular disorders. An interruption of therapy may be necessary.
Serious gastrointestinal toxicity has been reported with gefitinib use across clinical trials (n = 2,462), including severe diarrhea and GI perforation. Use gefitinib with caution in patients at risk for GI perforation. Patients with pre-existing diarrhea or dehydration should be treated prior to receiving gefitinib. Hold gefitinib therapy for severe or persistent diarrhea; an interruption or discontinuation of therapy may be necessary. Also, monitor patients for symptoms of GI perforation and permanently discontinue gefitinib if it occurs.
Serious rash has been reported with gefitinib therapy, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme. Monitor patients for the development of severe cutaneous reactions; interrupt or discontinue therapy if the patient develops severe bullous, blistering, or exfoliating conditions.
Although there are no adequate and well-controlled studies in pregnant women, gefitinib is considered a potential teratogen in humans because animal studies found gefitinib to be teratogenic at doses below those recommended for human use. Females of reproductive potential should use effective contraception during treatment with gefitinib and for at least 2 weeks after the last dose. Advise pregnant women of the potential hazard to the fetus or risk for pregnancy loss. Studies in rats showed that gefitinib crossed the placenta and led to a reduction in the number of live offspring at doses approximately 20% of the recommended human dose; at doses approximating the human dose on a mg/m2 bases, this effect was accompanied by high neonatal mortality. Reduced fetal weight has also been reported in rabbits at doses about twice the recommended human dose.
Counsel patients about the reproductive risk and contraception requirements during gefitinib treatment. Gefitinib 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 gefitinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of gefitinib. Women who become pregnant while receiving gefitinib should be apprised of the potential hazard to the fetus. In addition, based on animal data, gefitinib may result in reduced fertility (infertility) in females of reproductive potential.
Due to the potential for serious adverse reactions in nursing infants from gefitinib, advise women to discontinue breast-feeding during treatment. It is not known whether gefitinib is present in human milk, although many drugs are excreted in human milk.
For the first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test:
NOTE: If EGFR exon 19 deletions or exon 21 (L858R) substitution mutations are not detected in a plasma specimen, test tumor tissue if available. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: www.fda.gov/CompanionDiagnostics.
Oral dosage:
Adults: 250 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, single-arm, open-label clinical trial, patients with metastatic EGFR mutation positive NSCLC who received gefitinib (n = 106) had an objective response rate (ORR) of 50% for a median duration of 6 months by blinded independent central review (BICR), and an ORR of 70% for a median duration of 8.3 months by investigator assessment; complete responses occurred in 0.9% and 1.9% of patients, respectively. The results of this study were supported by an exploratory analysis of a subset of EGFR positive patients (15%) with metastatic NSCLC (adenocarcinoma) from a multicenter, randomized, open-label clinical trial. In these patients, the median progression-free survival (PFS) by BICR was 10.9 months for a median duration of 9.6 months in patients receiving first-line treatment with gefitinib compared with PFS of 7.4 months for a median duration of 5.5 months in those who received carboplatin plus paclitaxel (HR 0.54; 95% CI, 0.38 to 0.79). The ORR was 67% versus 41%, respectively.
For the treatment of recurrent or metastatic squamous-cell head and neck cancer*:
Oral dosage:
Adults: 250 or 500 mg/day PO has been studied; survival is not improved with gefitinib in this population. In a randomized, phase 3 trial in 486 patients, median overall survival (OS) was not improved with a daily dose of 250 mg (5.6 months) or 500 mg (6 months) compared with methotrexate 40 or 60 mg/m2 IV weekly (6.7 months). Additionally, significantly worse OS was reported with both doses of gefitinib compared with methotrexate therapy in a subgroup of patients who had platinum-resistant disease. Grade 3 to 5 tumor hemorrhage was reported in 4 patients (2.5%) who received gefitinib 250 mg per day and in 2 patients (1.2%) who received gefitinib 500 mg per day.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Gastrointestinal
-Grade 3 or higher diarrhea: Hold gefitinib treatment for up to 14 days. When symptoms resolve to grade 1 or less, resume therapy with gefitinib.
-Gastrointestinal perforation: Permanently discontinue gefitinib.
Ocular
-Signs and symptoms of severe or worsening ocular disorders, including keratitis: Hold gefitinib treatment for up to 14 days. When symptoms resolve to grade 1 or less, resume therapy with gefitinib.
-Persistent ulcerative keratitis: Permanently discontinue gefitinib.
Pulmonary
-Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever): Hold gefitinib treatment for up to 14 days. When symptoms resolve to grade 1 or less, resume therapy with gefitinib.
-Confirmed interstitial lung disease: Permanently discontinue gefitinib.
Skin/Soft Tissue
-Grade or higher 3 skin reactions: Hold gefitinib treatment for up to 14 days. When symptoms resolve to grade 1 or less, resume therapy with gefitinib.
Maximum Dosage Limits:
-Adults
250 mg per day PO.
-Geriatric
250 mg per day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment:
No dosage adjustment is necessary.
Treatment-Related Hepatotoxicity:
-Grade 2 or higher increases in ALT or AST: Hold gefitinib treatment for up to 14 days. When symptoms resolve to grade 1 or less, resume therapy with gefitinib.
-Severe hepatic impairment: Permanently discontinue gefitinib.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abiraterone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with abiraterone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and abiraterone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Acetaminophen; Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
Adagrasib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with adagrasib is necessary; the risk is increased in CYP2D6 poor metabolizers. Gefitinib is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor. Coadministration with another strong CYP3A inhibitor increased gefitinib exposure by 80%. The mean exposure of gefitinib was 2-fold higher in healthy CYP2D6 poor metabolizers compared to extensive metabolizers.
Aluminum Hydroxide: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Aluminum Hydroxide; Magnesium Carbonate: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Aluminum Hydroxide; Magnesium Trisilicate: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Antacids: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Apalutamide: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with apalutamide is necessary. If apalutamide is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of gefitinib. Patients receiving both a CYP3A inhibitor plus gefitinib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form and CYP3A inhibitor strength. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP2D6 and CYP3A substrate; gefitinib is a weak CYP2D6 inhibitor.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Avoid coadministration of sodium bicarbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of sodium bicarbonate. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of ranitidine with sodium bicarbonate to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Aspirin, ASA; Omeprazole: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
Atazanavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with atazanavir is necessary. Gefitinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Atazanavir; Cobicistat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with atazanavir is necessary. Gefitinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Berotralstat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with berotralstat is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and berotralstat is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Bupropion: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with bupropion is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and bupropion is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Bupropion; Naltrexone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with bupropion is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and bupropion is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Calcium Carbonate: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Major) Avoid coadministration of famotidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Calcium Carbonate; Magnesium Hydroxide: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Calcium Carbonate; Simethicone: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Calcium; Vitamin D: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Capivasertib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with capivasertib is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and capivasertib is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Carbamazepine: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with carbamazepine is necessary. If carbamazepine is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Ceritinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ceritinib is necessary. Gefitinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Chloramphenicol: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with chloramphenicol is necessary. Gefitinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cimetidine: (Major) Avoid coadministration of cimetidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of cimetidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Cinacalcet: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cinacalcet is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and cinacalcet is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Clarithromycin: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Cobicistat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Dacomitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with dacomitinib is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and dacomitinib is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Darunavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Darunavir; Cobicistat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Delavirdine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with delavirdine is necessary; the risk is increased in CYP2D6 poor metabolizers. Gefitinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. Based on in vitro data, gefitinib is also metabolized to O-desmethyl gefitinib by CYP2D6 and delavirdine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends additional precautions based on exposure in patients with poor CYP2D6 metabolism.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of dexlansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Dextromethorphan; Bupropion: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with bupropion is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and bupropion is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with quinidine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and quinidine is strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Dronedarone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with dronedarone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and dronedarone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Duloxetine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with duloxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and duloxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Eliglustat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with eliglustat is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and eliglustat is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Encorafenib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with encorafenib is necessary. If encorafenib is discontinued, gefitinib at a dose of 250 mg once daily may be resumed seven days later. Gefitinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer reduced gefitinib exposure by 83%.
Enzalutamide: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with enzalutamide is necessary. If enzalutamide is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Escitalopram: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with escitalopram is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and escitalopram is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Esomeprazole: (Major) Avoid coadministration of esomeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of esomeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Famotidine: (Major) Avoid coadministration of famotidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Fedratinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fedratinib is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fedratinib is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Fluoxetine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fluoxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fluoxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Fosamprenavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fosamprenavir is necessary. Gefitinib is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Fosphenytoin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with fosphenytoin is necessary. If fosphenytoin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Grapefruit juice: (Moderate) Instruct patients they may experience increased side effects from gefitinib if they regularly consume grapefruit juice. Gefitinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Ibuprofen; Famotidine: (Major) Avoid coadministration of famotidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Ibuprofen; Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
Idelalisib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with idelalisib is necessary. Gefitinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Indinavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with indinavir is necessary. Gefitinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with rifampin is necessary. If rifampin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin reduced gefitinib exposure by 83%.
Isoniazid, INH; Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with rifampin is necessary. If rifampin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin reduced gefitinib exposure by 83%.
Itraconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with itraconazole is necessary. Gefitinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased gefitinib exposure by 80%.
Ketoconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ketoconazole is necessary. Gefitinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Lansoprazole: (Major) Avoid coadministration of lansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of lansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of gefitinib may occur if given with letermovir. Closely monitor for gefitinib-related adverse reactions in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Gefitinib is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased mean exposure of gefitinib by 80%.
Levoketoconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ketoconazole is necessary. Gefitinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Lonafarnib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with lonafarnib is necessary. Gefitinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Lopinavir; Ritonavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Lumacaftor; Ivacaftor: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with lumacaftor; ivacaftor is necessary. If lumacaftor; ivacaftor is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Lumacaftor; Ivacaftor: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with lumacaftor; ivacaftor is necessary. If lumacaftor; ivacaftor is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Magnesium Hydroxide: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Mifepristone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with chronic mifepristone therapy is necessary. Gefitinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Mirabegron: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with mirabegron is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and mirabegron is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Mitotane: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with mitotane is necessary. If mitotane is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Naproxen; Esomeprazole: (Major) Avoid coadministration of esomeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of esomeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Nefazodone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with nefazodone is necessary. Gefitinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Nelfinavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with nelfinavir is necessary. Gefitinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Niraparib; Abiraterone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with abiraterone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and abiraterone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Nizatidine: (Major) Avoid coadministration of nizatidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of nizatidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of an H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Olanzapine; Fluoxetine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fluoxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fluoxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Omeprazole: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Omeprazole; Sodium Bicarbonate: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Major) Avoid coadministration of sodium bicarbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of sodium bicarbonate. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of ranitidine with sodium bicarbonate to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
Panobinostat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with panobinostat is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and panobinostat is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Pantoprazole: (Moderate) Avoid coadministration of pantoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of pantoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Paroxetine: (Moderate) Monitor for an increase in gefitinib- and paroxetine-related adverse reactions, including serotonin syndrome, if coadministration is necessary. Concomitant use may increase exposure of both drugs; the risk of gefitinib-related adverse reactions is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and is a weak CYP2D6 inhibitor; paroxetine is a CYP2D6 substrate and strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
Phenobarbital: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenobarbital is necessary. If phenobarbital is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenobarbital is necessary. If phenobarbital is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Phentermine; Topiramate: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with topiramate. Gefitinib is metabolized significantly by CYP3A4 and topiramate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing topiramate, such as phentermine; topiramate. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
Phenytoin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenytoin is necessary. If phenytoin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Pimozide: (Moderate) Monitor for an increase in pimozide-related adverse reactions if coadministration with gefitinib is necessary. Pimozide is a CYP2D6 substrate with a narrow therapeutic range and gefitinib is a CYP2D6 inhibitor. While the manufacturer has provided no guidance regarding pimozide use with mild or moderate CYP2D6 inhibitors, concurrent use of the drug with more potent inhibitors of CYP2D6 is contraindicated. Elevated concentrations of pimozide can lead to QT prolongation, ventricular arrhythmias, and sudden death.
Posaconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with posaconazole is necessary. Gefitinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Primidone: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with primidone is necessary. If primidone is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Propafenone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with propafenone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and propafenone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Quinidine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with quinidine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and quinidine is strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Quinine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with quinine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and quinine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Rabeprazole: (Major) Avoid coadministration of rabeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of rabeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Ranitidine: (Major) Avoid coadministration of ranitidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of ranitidine. Gefitinib exposure is affected by gastric pH. Coadministration of high doses of ranitidine with sodium bicarbonate to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
Ranolazine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ranolazine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and ranolazine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Ribociclib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ribociclib is necessary. Gefitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ribociclib is necessary. Gefitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with rifampin is necessary. If rifampin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin reduced gefitinib exposure by 83%.
Rifapentine: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with rifapentine is necessary. If rifapentine is discontinued, gefitinib at a dose of 250 mg once daily may be resumed seven days later. Gefitinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Ritonavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Rolapitant: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with rolapitant is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and rolapitant is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Saquinavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with saquinavir is necessary. Gefitinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sodium Bicarbonate: (Major) Avoid coadministration of sodium bicarbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of sodium bicarbonate. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of ranitidine with sodium bicarbonate to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
St. John's Wort, Hypericum perforatum: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with St John's Wort is necessary. If St John's Wort is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and St John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Terbinafine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with terbinafine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and terbinafine is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Thioridazine: (Contraindicated) The concomitant use of gefitinib and thioridazine is contraindicated; exposure to gefitinib may also increase. Thioridazine is a CYP2D6 substrate and gefitinib is a weak-to-moderate CYP2D6 inhibitor. Concomitant use may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsades de pointes (TdP)-type arrhythmias. Additionally, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and thioridazine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Tipranavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with tipranavir is necessary; the risk is increased in CYP2D6 poor metabolizers. Gefitinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. Based on in vitro data, gefitinib is also metabolized to O-desmethyl gefitinib by CYP2D6 and tipranavir is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Topiramate: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with topiramate. Gefitinib is metabolized significantly by CYP3A4 and topiramate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing topiramate, such as phentermine; topiramate. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
Tucatinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with tucatinib is necessary. Gefitinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Vonoprazan: (Major) Avoid concomitant use of gefitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of gefitinib reducing its efficacy.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of gefitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of gefitinib reducing its efficacy.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of gefitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of gefitinib reducing its efficacy. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Voriconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with voriconazole is necessary. Gefitinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Warfarin: (Moderate) Regularly monitor INR regularly and watch carefully for signs and symptoms of bleeding if gefitinib and warfarin are used concomitantly. Elevated INR and/or hemorrhage have been reported in some patients taking warfarin while on gefitinib therapy.
Gefitinib is a synthetic anilinoquinazoline that is a selective inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK). The activity of protein tyrosine kinases is tightly regulated since they function as mediators of cell growth, differentiation, and death. Exon 19 deletion and exon 21 (L858R) substitution mutation are activating mutations within NSCLC cells, and have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors, and facilitating the process of metastasis. The binding affinity of gefitinib for EGFR exon 19 deletion or exon 21 (L858R) substitution mutations is higher than its affinity for wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations. The effect of gefitinib on other tyrosine kinase receptors has not been fully characterized.
Gefitinib reversibly binds to the ATP-binding site and completely inhibits autophosphorylation by EGFR-TK. This results in blockage of downstream EGFR signal transduction pathways, cell cycle arrest, and inhibition of angiogenesis. The skin rash adverse reaction commonly seen with gefitinib is thought to be a result of inhibition of EGRF-positive epidermal keratinocytes and other skin cells that are dependent upon EGFR for normal cellular growth and activity; the appearance of skin rash appears to correlate with clinical activity of the drug.
Gefitinib is administered orally. In vitro binding to plasma proteins, primarily albumin and alpha-1-acid glycoprotein, is 90% and independent of drug concentrations. Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life of 48 hours after intravenous administration. Steady-state plasma concentrations are achieved within 10 days after daily dosing. Excretion is predominantly via the feces (86%), with renal elimination of the drug and metabolites accounting for less than 4% of the administered dose.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6
Gefitinib undergoes significant hepatic metabolism, predominantly via the cytochrome P450 isoenzyme 3A4 (CYP3A4). Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. A dose adjustment is necessary in patients receiving strong CYP3A4 inducers, with extra monitoring in place for patients receiving strong CYP3A4 inhibitors. Additionally, in vitro CYP2D6 metabolizes gefitinib to its major (14%) active metabolite, O-desmethyl gefitinib, which has similar EGFR-tyrosine kinase activity to gefitinib, but only 1/14 of the potency in a cell-based assay. Eight metabolites have been identified in human plasma, with only O-desmethyl gefitinib having exposure comparable to gefitinib; five metabolites have been fully identified in fecal extracts. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and the mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers; this may be relevant as some adverse drug reactions are related to higher exposure of gefitinib. Monitor known CYP2D6 poor metabolizers for an increased incidence of adverse effects; however, a dose adjustment is not recommended by the manufacturer. The impact of drugs that inhibit CYP2D6 has not been studied, but similar precautions should be in place.
In human liver microsome studies, gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43% at the highest concentration studied (5,000 ng/mL). In another pharmacokinetic study, gefitinib administration at twice the recommended dose increased the AUC of metoprolol, a CYP2D6 substrate, by 35% which was not statistically significant. The investigators concluded that gefitinib is a weak inhibitor of CYP2D6 that is unlikely to exert a clinically relevant effect on CYP2D6 substrates; however, the potential should be considered in CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated. The manufacturer of gefitinib does not recommend precautions in patients receiving CYP2D6 substrates. No inhibitory effects were seen on CYP1A2, CYP2C9, or CYP3A4 at concentrations ranging from 2,000 to 5,000 ng/mL. Gefitinib is a P-glycoprotein (P-gp) substrate, but it is unlikely to influence gefitinib absorption as P-gp is saturated at higher concentrations.
-Route-Specific Pharmacokinetics
Oral Route
Gefitinib is slowly absorbed with peak plasma levels occurring 3 to 7 hours after dosing with a mean bioavailability of 60%; bioavailability is not meaningfully altered by food. However, the mean AUC of gefitinib was decreased by 47% in healthy subjects when coadministered with high doses of ranitidine and sodium bicarbonate to maintain the gastric pH above 5. Administration of gefitinib with proton pump inhibitors, H2-blockers, and antacids should be avoided if possible. If concomitant use is unavoidable, administration should be separated by 6 hours for antacids and H2-blockers and by 12 hours for proton pump inhibitors. Inter-subject variability (coefficient of variation) for AUC in healthy subjects was 67%. Daily oral administration of gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration.
Intravenous Route
Gefitinib is extensively distributed throughout the body, with a mean steady state volume of distribution of 1,400 liters after intravenous administration.
-Special Populations
Hepatic Impairment
The mean systemic exposure of gefitinib was increased by 40% in patients with mild hepatic impairment (Child Pugh A; n = 10), 263% in patients with moderate hepatic impairment (Child Pugh B; n = 10), and 166% in patients with severe hepatic impairment (Child Pugh C, n = 10) compared to patients with normal hepatic function (n = 10). In a separate study, the pharmacokinetics of gefitinib were similar in patients with liver metastases and normal liver function (n = 14) compared to patients with liver metastases and moderate hepatic impairment (n = 13).
Renal Impairment
Less than 4% of gefitinib and its metabolites are excreted via the kidney. Creatinine clearance (CrCL) greater than 20 mL/min does not have a clinically meaningful effect on the pharmacokinetics of gefitinib, based on a population analysis. No clinical studies have been conducted with gefitinib in patients with severely compromised renal function.
Pediatrics
No clinical studies have been conducted with gefitinib in pediatric patients.
Geriatric
Based on population pharmacokinetic analyses, age does not have a clinically meaningful effect on the predicted steady state trough concentration of gefitinib.
Gender Differences
Based on a population pharmacokinetics analysis of one clinical study, gefitinib exposure was 27% higher in women compared to men; this difference was not identified in the analyses of other gefitinib studies. A does adjustment based on gender is not recommended.
Ethnic Differences
Based on population pharmacokinetic analyses, ethnicity does not have a clinically meaningful effect on the predicted steady state trough concentration of gefitinib.
Obesity
Based on population pharmacokinetic analyses, body weight does not have a clinically meaningful effect on the predicted steady state trough concentration of gefitinib.