Gefitinib, being a selective inhibitor of epidermal growth factor receptor tyrosine kinase, expression of which is observed in many solid tumors, inhibits tumor growth, metastasis and angiogenesis, and accelerates apoptosis of tumor cells. Inhibits the growth of various human tumor cell lines and increases the antitumor activity of chemotherapeutic drugs, radiation and hormone therapy.
Clinical data suggest that gefitinib has an objective antitumor effect and statistically significantly increases the time to disease progression in patients with locally advanced or metastatic non-small cell lung cancer.
Mechanism of Action
Epidermal growth factor receptor (rEGF) is expressed on the cell surface of both normal and cancer cells and is involved in the processes of cell growth and proliferation. Some rEGF activating mutations (exon 19 deletion or L858R exon 21 point mutation) in non-small cell lung cancer (NSCLC) cells have been identified as contributing to tumor cell growth stimulation, apoptosis blockade, increased angiogenic factor production and facilitation of metastasis processes.
Gefitinib reversibly inhibits the kinase activity of wild-type rEFR and some activating mutations by preventing autophosphorylation of tyrosine residues bound to the receptor, thus inhibiting further signal transduction and blocking rEFR-dependent proliferation. The affinity of gefitinib to rEFR exon 19 deletion or the L858R point mutation of exon 21 is higher than its affinity to wild-type rEFR. Gefitinib also inhibits insulin-like growth factor and platelet-mediated growth factor signaling at clinically relevant concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.
Drug Interactions
Strong CYP3A4 inducers. Concomitant use of rifampicin (600 mg once daily for 16 days), a strong CYP3A4 inducer, and gefitinib (single dose of 500 mg, on day 10 after gefitinib administration) reduced the mean AUC of gefitinib by 83% (see "Interactions").
CYP3A4 inhibitors. Simultaneous use of CYP3A4 inhibitor itraconazole (200 mg 1 time per day for 12 days) and gefitinib (single dose, 250 mg, on day 4 of itraconazole) in healthy men increased average AUC of gefitinib by 80% (see "Interaction").
Drugs affecting gastric pH. Co-administration of high doses of ranitidine and sodium bicarbonate (to maintain gastric pH above 5) in healthy volunteers reduced the average AUC of gefitinib by 47% (see "Interaction").
In studies on human liver microsomes, gefitinib had no inhibitory effect on CYP1A2, CYP2C9 and CYP3A4 activity in the concentration range from 2 to 5000 ng/ml. At the highest concentration studied (5000 ng/mL), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43%.
Exposure to metoprolol, a CYP2D6 substrate, was increased by 30% when administered on day 15 of gefitinib (500 mg daily for 28 days) in patients with solid tumors.
Indications
Metastatic non-small cell lung cancer with rEFR exon 19 deletions or exon 21 (L858R) replacement mutations (first-line therapy).
Contraindications
Restriction of use. Safety and efficacy of gefitinib have not been established in patients with metastatic non-small cell lung cancer whose tumors have rEFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.
Use in pregnancy and lactation
The FDA fetal category of action is D.
Pregnancy
Risk Summary. Based on the mechanism of action and animal data, gefitinib may cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis to weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Pregnant women should be informed of the potential danger to the fetus or the potential risk of pregnancy loss.
Women of reproductive potential should use effective contraception during gefitinib use and for at least 2 weeks after completion of therapy. Use of gefitinib may result in decreased fertility in women of reproductive potential.
The background risk of serious birth defects and miscarriage for the indicated population is unknown, but the background risk of serious birth defects in the general US population is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies.
Animal data. A single-dose study in rats showed that gefitinib penetrates the placenta after oral administration at a dose of 5 mg/kg (30 mg/m2, which is approximately 0.2 of the recommended human dose per body surface area). When pregnant rats were given a dose of 5 mg/kg from the beginning of organogenesis until the end of weaning, a decrease in the number of live-born cubs was observed. This effect was intensified at a dose of 20 mg/kg (approximately the clinical dose for humans in terms of body surface area) and was accompanied by high neonatal mortality shortly after delivery. In rabbits, a dose of 20 mg/kg/day (240 mg/m2, approximately twice the recommended human dose per body surface area) caused fetal weight loss.
Breastfeeding
Risk Summary. It is not known whether gefitinib is excreted with breast milk. Animal studies show that gefitinib and its metabolites are present in rat milk at higher concentrations than in maternal plasma. Because of the possibility of serious adverse reactions in infants, women receiving gefitinib are advised to stop breastfeeding during treatment.
Data obtained on animals. After oral administration of 5 mg/kg dose to lactating rats, levels of gefitinib and its metabolites in milk were 11-19 times higher than in blood.
Side Effects
The following adverse reactions are discussed in more detail in the precautions section: interstitial lung disease, hepatotoxicity, GI perforation, severe or persistent diarrhea, eye disease including keratitis, bullous and exfoliative skin disease.
The following adverse reactions not listed above were reported when gefitinib was used in the NMSR studies (Study 2, Study 3, and Study 4): nausea (18%), asthenia (17%), fever (9%), alopecia (4.7%), bleeding (including nasal bleeding and hematuria) (4.3%), dry mouth (2%), dehydration (1.8%), increased blood creatinine levels (1.5%), allergic reactions including angioedema and urticaria (1.1%), palmar erythrodysesthesia syndrome (0.2%), and pancreatitis (0.1%).
Post-registration observation experience
During the post-registration period of gefitinib, the following adverse reactions were identified. Because these reactions were reported voluntarily from a population of unspecified size, it is not always possible to reliably estimate their frequency or establish a causal relationship to gefitinib exposure.
Renal and urinary tract disorders: cystitis, hemorrhagic cystitis.
Skin and subcutaneous tissue: cutaneous vasculitis.
Interaction
Drugs that affect gefitinib exposure
CYP3A4 inducers. Medicinal products, which are strong CYP3A4 inducers, increase gefitinib metabolism and decrease its plasma concentration. In patients receiving strong CYP3A4 inducers (e.g., rifampicin, phenytoin or tricyclic antidepressants) the dose should be increased to 500 mg/day and the dose should be resumed in 250 mg in 7 days after stopping the strong inducer.
CYP3A4 inhibitors. Drugs that are strong CYP3A4 inhibitors (e.g., ketoconazole and itraconazole) reduce metabolism of gefitinib and increase its plasma concentration. Adverse reactions in co-administration of strong CYP3A4 inhibitors and gefitinib should be controlled.
Drugs affecting gastric pH
Drugs that increase gastric pH (e.g., proton pump inhibitors, histamine H2-receptor antagonists and antacids) may decrease the plasma concentration of gefitinib. Concomitant use of gefitinib and proton pump inhibitors should be avoided. If concomitant use of proton pump inhibitors is necessary, gefitinib should be taken 12 hours after the last dose or 12 hours before the next dose of proton pump inhibitor. Gefitinib should be taken 6 hours after or 6 hours before taking an H2-receptor antagonist or antacid.
Bleeding in patients receiving warfarin
Increased INR and/or bleeding have been reported in some patients taking warfarin during therapy with gefitinib. Patients taking warfarin should be monitored regularly for changes in PV or INR.
Overdose
Symptoms: Twenty-three patients received gefitinib at weekly doses of 1,500 to 3,500 mg, and exposure did not increase with increasing dose. The adverse events were mostly mild to moderate in severity and were consistent with the known safety profile of gefitinib.
Treatment: If gefitinib overdose is suspected, maintenance therapy should be administered and the patient's condition monitored until clinical stabilization. There are no special measures and ways of treatment of gefitinib overdose.
Dosage and administration
Orally, the recommended dose is 250 mg once daily, regardless of meals, until disease progression or unacceptable toxicity occurs.
Precautions
Interstitial lung disease
Interstitial lung disease or adverse reactions similar to it (e.g., pulmonary infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis) occurred in 1.3% of 2462 patients who received gefitinib in clinical trials, of whom 0.7% had severity 3 or higher and 3 cases were fatal.
Gefitinib should be temporarily discontinued and immediately evaluated for interstitial lung disease in any patient with worsening respiratory symptoms, such as dyspnea, cough, and fever. Discontinue gefitinib completely if interstitial lung disease is confirmed.
Hepatotoxicity
In 11.4% of patients receiving gefitinib during clinical trials, elevated ALT levels, 7.9% of patients had elevated AST levels, and 2.7% of patients had elevated bilirubin levels. Grade 3 or higher liver abnormalities were observed in 5.1% (ALT), 3% (AST), and 0.7% (bilirubin) of patients. The incidence of fatal hepatotoxicity was 0.04%.
Periodic liver function testing should be performed, gefitinib should be temporarily discontinued in patients with impaired liver function, and its use should be completely discontinued in patients with severe hepatic impairment.
Gastrointestinal perforation
Gastrointestinal perforation was observed in 3 (0.1%) of 2462 patients who received gefitinib in clinical trials (see Adverse Effects). Gefitinib should be discontinued completely in patients who develop gastrointestinal perforation.
Form of release
Capsules 250 mg. 30 capsules in a cardboard box; 10 capsules in a blister.
Manufacturer
"Dong-Pha" South Korea.
Storage conditions
Keep at a temperature not exceeding 25°C.
Keep out of reach of children.
Shelf life
2 years.
Do not use after expiration date stated on the package.
