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DRUG INTERACTIONSIn two open, randomized, crossover trials in healthy male volunteers, the mean AUC concentration and Cmaxwere decreased by 83% and 65%, respectively, when patients (n = 18) were given 500 mg of gefitinib alone on day 10 of a 16-day dosing regimen of 600 mg/day of rifam-picin (e.g., Rimactone®, Geneva), a potent CYP-3A4 inducer. In the second trial, two cohorts (n = 24 each) received 500 mg or 250 mg of gefitinib on the fourth day of a 12-day dosing regimen of itraconzole (Janssen, Ortho Biotech) 200 mg/day, a potent CYP-3A4 inhibitor. In this group, the AUC concentration increased by 58% in the patients taking 250 mg and by 80% in those taking 500 mg; the Cmax increased by 32% in the 250-mg group and by 51% in the 500-mg group. Inducers of CYP-3A4 increase the metabolism of gefitinib and decrease its plasma concentrations, whereas inhibitors of CYP-3A4 decrease gefitinib metabolism and increase gefi-tinib plasma concentrations.

When gefitinib 500 mg/day was given in combination with metoprolol (Lopres-sor®, Novartis) to patients with solid tumors for 28 days, there was a 30% increase in levels of metoprolol, which is a substrate of CYP-2D6. Gefitinib inhibited CYP-2C19 by 24% and CYP-2D6 by 43% at study concentrations of 5,000 ng/ml. (Zantac canadian, Glaxo-SmithKline) with sodium bicarbonate, used to maintain the gastric pH above 5.0, reduced the mean gefitinib AUC concentration by 44%. Elevations in the International Normalized Ratio (INR) and bleeding events have been reported in patients taking warfarin sodium (DuPont) while they were also taking gefitinib.


Gefitinib has been well tolerated in phase I,, II, and III clinical trials in patients with NSCLC. The most commonly reported ADEs were dose-dependent and reversible skin rash, gastrointestinal symptoms (diarrhea, nausea, vomiting, constipation, abdominal pain), anemia, and elevated hepatic transaminases. Other common reactions in the study by Ranson et al. were conjunctivitis, dyspnea, increased cough, asthenia, somnolence, and headache.

There were reports of eye pain and corneal erosion or ulcer, sometimes in association with aberrant eyelash growth. In a study by Herbst et al., one patient withdrew from the study because of corneal epithelial damage, caused by an ingrown eyelash; however, the damage was reversed following gefitinib withdrawal and supportive care measures.

Postmarketing studies in Japan have reported the occurrence of interstitial lung disease (ILD).

Skin Reactions

In all three phases of the clinical trials, skin reactions occurred in the majority of patients. Reactions generally occurred between days 10 and 14 of treatment and resolved during the off-treatment period, with a decrease in frequency observed over each treatment period. Most reactions were grade 1 or 2 acne-like rash on an erythematous base. Rashes were transient in most cases, and there were no reports of scarring or other permanent skin chan-ges. Grade 3 or 4 reactions were observed primarily at doses greater than 400 mg/day.


Diarrhea also occurred in all three phases, most commonly during the first treatment period. It was described as a watery or loose stool that was negative for blood or mucus. Usually, grade 1 or 2 diarrhea was observed, but doses as low as 300 mg/day were associated with grade 3. Diarrhea usually resolved with cessation of therapy and supportive care measures.

Pulmonary Toxicity


(Interstitial Lung Disease)

In Japan, acute ILD occurred in about 1% to 2% of patients receiving gefitinib. Overall, ILD has occurred in approximately 1% of patients receiving gefitinib, and fatalities have occurred in about one-third of patients with ILD, generally in those who received previous radiation therapy (31%), earlier chemotherapy (57%), and no prior therapy (12%). Symptoms of ILD include acute-onset dyspnea and an occasional cough or low-grade fever that may worsen and require hos-pitalization. Increased mortality was observed in patients with lung co-morbidities whose condition deteriorated with gefitinib therapy.


Gefitinib is administered as an oral 250-mg tablet to be taken with or without food. In clinical trials, higher doses resulted in greater toxicity and did not provide a superior response. Dosage adjustments are not required on the basis of the patient’s age, weight, sex, ethnicity, or renal function. In patients with hepatic impairment caused by liver metastases, bioavailability levels were similar to those observed in patients with normal liver function, signifying that there is no need for dose modification. Gefitinib therapy should be withheld if an acute onset or worsening of pulmonary symptoms occurs, and it should be discontinued if ILD is confirmed. In patients receiving a potent CYP-3A4 inducer, such as rifampicin or phenytoin (Diantin®, Pfizer), clinicians should consider increasing the dose of gefitinib to 500 mg daily and should monitor patients for drug reactions, clinical response, and ADEs. Therapy should be withheld if eye pain or other related eye symptoms occur, and the aberrant eyelash, if present, should be removed. canadian pharmacy viagra


Gefitinib is the first in a new class of agents. It is indicated as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies. Unlike the side-effect profile associated with most other cytotoxic agents, gefitinib has an acceptable tolerability profile, and most drug- related ADEs are mild and reversible 10,13,14,15-20 In clinical studies, improved quality of life seemed to correlate with those patients who had partial responses to therapy or stable disease. Gefitinib is a safe and effective second-line treatment option available for patients with advanced NSCLC.

Category: Drugs


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