Gefitinib

Mechanism of effect

Gefitinib is a tyrosine kinase inhibitor (TKI) which reversibly inhibits kinase activity of wild-type and select activation mutations of epidermal growth factor receptor (EGFR). EGFR is expressed on cell surfaces of normal and cancer cells and has a role in cell growth and proliferation. Gefitinib prevents autophosphorylation of tyrosine residues associated with the EGFR receptor, which blocks downstream signaling and EGFR-dependent proliferation. Gefitinib has a higher binding affinity for EGFR exon 19 deletion and exon 21 (L858R) substitution mutation than for wild-type EGFR.

Pharmacodynamic

Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.

Pharmacokinetics

Oral bioavailability, mean: 60%

Peak plasma concentration: 3-7 hr

Steady-state achieved: 10 days

Protein bound: 90%

Vd: 1400 L

Extensive hepatic metabolism, predominantly by CYP3A4

Major active metabolite component was O-desmethyl gefitinib produced by CYP2D6 metabolism and accounted for 14% of the dose

Half-life: 48 hr

Excretion: 86% feces; <4% urine

Drug indications

Non-small Cell Lung Cancer

First-line treatment of metastatic non-small cell lung cancer (NSCLC) in tumors with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected in tumor or plasma specimen by an approved test.

Dosage

250 mg PO qDay until disease progression or unacceptable toxicity

Drug contraindications

Hypersensitivity to this drug

Hypersensitivity to drug or any ingredient

Side effects

Insomnia , Diarrhea , Proteinuria , vomiting , Angioedema , asthenia , urticaria , fever , Stevens-Johnson syndrome , anorexia , hemorrhage , peripheral nephropathy , liver failure , itching , nail disorders , renal failure , skin rush , tiredness , Leukopenia

Insomnia ,fatigue ,Dermatological reaction , skin rash ,xeroderma , pruritus , paronychia ,acne vulgaris ,alopecia ,Diarrhea , anorexia , nausea , decreased appetite ,vomiting , stomatitis , constipation ,Proteinuria ,Increased serum AST , increased serum ALT, Weakness ,Hypoesthesia , peripheral sensory neuropathy , peripheral neuropathy ,Nail disease , acneiform eruption ,Dehydration ,Xerostomia ,Cystitis ,Anemia ,pulmonary hemorrhage , hemorrhage ,neutropenia , leukopenia , thrombocytopenia ,Increased serum bilirubin ,Myalgia , arthralgia ,Eye disease,Increased serum creatinine , Cough , interstitial pulmonary disease ,Fever ,Angioedema, bullous skin disease, corneal erosion (reversible; may be associated with aberrant eyelash growth), decreased white blood cell count, erythema multiforme, fulminant hepatitis, gastrointestinal perforation, hemorrhagic cystitis, hepatic failure, hepatitis, hypersensitivity angiitis, hypersensitivity reaction, keratitis, keratoconjunctivitis sicca, pancreatitis, renal failure, skin fissure, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Interactions

Dexlansoprazole , Atomoxetine , Aripiprazole , Asparaginase , Amiodarone , Aprepitant , Epirubicin , Somatrem , tucatinib , ubrogepant , telotristat , voxelotor , Daclizumab , Brentuximab , pegaspargase , rimegepant , lemborexant , butalbital , fosaprepitant , cenobamate , st. john's wort , tazemetostat , Cannabidiol , vemurafenib , ozanimod , lefamulin , selpercatinib , givosiran , conivaptan , Omacetaxine , Aminoglutethimide (Oral) , bedaquiline , Dasatinib , nafcillin , Anisindione , Rucaparib , Troleandomycin , Ceritinib , riociguat , Methyl aminolevulinate , Alpelisib , Fedratinib , ivosidenib , Crizotinib , Lorlatinib , Dacomitinib , trabectedine , Secobarbital , Duvelisib , Apalutamide , pexidartinib , elagolix , Cevimeline , Letermovir , Fesoterodine , Binimetinib , Butabarbital , Isavuconazonium , Aminolevulinic acid topical , Verteporfin , Troglitazone , cobicistat , Delavirdine , Fostamatinib , Telaprevir , Etravirine , Dabrafenib , Darifenacin , Mibefradil , aminolevulinic acid oral , Idelalisib , Ivacaftor , brigatinib , Clofarabine , Efavirenz , Bexarotene , Dicoumarol , Ribociclib , echinacea , Armodafinil , Felbamate , Fosphenytoin , Nizatidine , Telithromycin , boceprevir , Phenylbutazone , Palifermin , Indinavir , nelfinavir , nevirapine , mitotane , Amprenavir , Fosamprenavir , Mifepristone , teriflunomide , codeine , Nefazodone , dronedarone , ritonavir , saquinavir , Darunavir , Donepzil , Pentobarbital , Amobarbital , Lomitapide , Mipomersen , Bicalutamide , sulfinpyrazone , Rifabutin , Rifapentine , Atazanavir , Ranolazine , Ketoconazole , Clarithromycin , Chloramphenicol , Clotrimazole , Interferon beta-1a , Enzalutamide , Nilotinib , Somatropin-Human Growth hormone , Warfarin , Verapamil , Voriconazole , Carbamazepine , Methotrexate , Methoxalen , Modafinil , Miconazole , naltrexone , Nifedipine , Fluconazole , Phenobarbital , Phenytoin , Griseofulvin , Lansoprazole , Lapatinib , Zafirlukast , Cimetidine , Ciprofloxacin , Cyclosporine , Famotidin , Fluvoxamine , Dexamethasone , Duloxetine , Diltiazem , Rabeprazole , Ranitidine , Rifampin , Tolterodine , Timolol , Thioridazine , Thioguanine , Danazol , Deferasirox , Interferon beta-1b , Bosentan , Bismuth , Primidone , Pantoprazole , Posaconazole , Erythromycin , Esomeprazole , Oxecarbazepin , Itraconazole , Isoniazid , Imatinib , Remdesivir , talazoparib

aminolevulinic acid topical-asparaginase erwinia chrysanthemi-asparaginase escherichia coli-black cohosh-calaspargase pegol-lusutrombopag

Alerts

-Withhold for up to 14 days following adverse effects

Acute onset or worsening pulmonary symptoms (dyspnea, cough, fever)
≥Grade 2 ALT and/or AST elevations
≥Grade 3 diarrhea
Signs and symptoms of severe or worsening ocular disorders including keratitis(eg, keratitis, corneal erosion, aberrant eyelash growth, conjunctivitis, blepharitis, dry eye);
≥Grade 3 skin reactions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme
May resume gefitinib when adverse effect fully resolves or improves to Grade 1

-Permanently discontinue for

Confirmed interstitial lung disease(eg, lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis)
Severe hepatic impairment
Gastrointestinal perforation
Persistent ulcerative keratitis

-Coadministration with strong CYP3A4 inducers

Increase dose to 500 mg PO qDay in the absence of severe adverse drug reactions
Resume 250 mg qDay after discontinuation of the strong CYP3A4 inducer

-CYP2D6 metabolizes gefitinib to O-desmethyl gefitinib in vitro. No dose adjustment is recommended in patients with a known CYP2D6 poor metabolizer genotype, but these patients should be closely monitored for adverse reactions

Points of recommendation

-May take with or without food

- Do not take a missed dose within 12 hr of the next scheduled dose

-Difficulty swallowing

Immerse tablet in 4-8 ounces of water and stir for approximately 15 minutes
Immediately drink the liquid or administer through a NG tube
Rinse the container with an additional 4-8 ounces of water and immediately drink or administer through the NG tube to assure complete dose

Pregnancy level

Forbidden

Based on its mechanism of action and animal data, gefitinib can cause fetal harm when administered to a pregnant woman

Advise females of reproductive potential to use effective contraception during treatment with gefitinib and for at least 2 weeks following completion of therapy

Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy

Breast feeding warning

Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma

Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment

GENERIC DRUG INFO

suppliment

Drug information of Gefitinib