Side Effects of Iressa (gefitinib)

Iressa (gefitinib) is a tyrosine kinase inhibitor used to treat several types of lung cancer. 

It works by preventing lung cancer cells from growing and multiplying. Many cells, including cancer cells, have receptors on their surfaces for epidermal growth factor (EGF), a protein that is normally produced by the body and that promotes the growth and multiplication of cells. 

When EGF attaches to epidermal growth factor receptors (EGFRs), it causes an enzyme called tyrosine kinase to become active within the cells. Tyrosine kinase triggers chemical processes that cause the cells, including cancer cells, to grow, multiply, and spread. 

Iressa attaches to EGFRs and thereby blocks the attachment of EGF and the activation of tyrosine kinase. This mechanism for stopping cancer cells from growing and multiplying is very different from the mechanisms of chemotherapy and hormonal therapy.

Common side effects of Iressa include

• diarrhea,
• vomiting,
• skin reactions,
• nail disorders,
• inflammation of the lining of the mouth,
• decreased appetite, and
• eye irritation. 

Serious side effects of Iressa include

• interstitial lung disease (symptoms include new or worsening cough, fever, or difficulty in breathing) and
• severe or persistent diarrhea,
• nausea,
• loss of appetite, or
• vomiting.

Drug interactions of Iressa include warfarin, because Iressa may increase its blood-thinning effects and increase the risk of bleeding. 

Patients who receive drugs that increase an enzyme in the liver called CYP 3A4 that destroys Iressa (for example, rifampin or phenytoin) may need a higher dose of Iressa to maintain the effectiveness of Iressa. 

Similarly, patients who receive drugs that reduce CYP 3A4, for example, ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, ritonavir, nelfinavir, indinavir, nefazodone, as well as grapefruit juice, may need a lower dose of Iressa to prevent side effects from increased levels of Iressa. 

Iressa should not be used by pregnant women. It is unknown if Iressa is secreted in breast milk. 

Since there is a possibility of toxicity in nursing infants, it is recommended breastfeeding be stopped if the mother is treated with Iressa.

About one in one hundred persons receiving gefitinib develop a potentially serious lung condition called interstitial lung disease that causes inflammation within the lung. Therefore, patients taking gefitinib who develop new or worsening cough, fever, or difficulty in breathing should contact their physician immediately.

Eye irritation has been observed in patients receiving gefitinib, and patients who develop the onset of new eye symptoms should contact their physician.

All patients taking gefitinib should seek medical advice promptly if they develop severe or persistent

• diarrhea,
• nausea,
• loss of appetite, or
• vomiting.

The following adverse drug reactions are discussed in more detail in other sections of the labeling:

• Interstitial Lung Disease
• Hepatotoxicity
• Gastrointestinal Perforation
• Severe or Persistent Diarrhea
• Ocular Disorders including Keratitis
• Bullous and Exfoliative Skin Disorders

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Iressa is based on the data from 2462 patients with NSCLC who received Iressa 250 mg daily monotherapy in three randomized clinical studies (Study 2, Study 3 and Study 4). Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment or any evidence of clinically active interstitial lung disease were excluded from these studies.

Controlled Studies

• Study 2 was a randomized, multicenter, open-label trial in which 1217 patients were randomized to receive first-line treatment for metastatic NSCLC; 607 patients received Iressa 250 mg daily and 589 patients received carboplatin/paclitaxel.
• The median duration of treatment with Iressa was 5.9 months.
• The study population characteristics were:
  • median age 57 years,
  • age less than 65 years (73%),
  • female (79%),
  • Asian (100%),
  • NSCLC adenocarcinoma histology (100%),
  • never smoker (94%),
  • light ex-smoker (6%),
  • ECOG PS 0 or 1 (90%).
• Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which 1692 patients were randomized to receive second- or third-line treatment for metastatic NSCLC; of which 1126 patients received Iressa 250 mg daily and 562 patients received placebo. The median duration of treatment with Iressa was 2.9 months.
• The study population characteristics were:
  • median age 62 years,
  • age less than 65 years (60%),
  • female (33%),
  • Caucasian (75%),
  •  Asian (21%),
• NSCLC adenocarcinoma histology (48%),
  • never smoker (22%),
  • ECOG PS 0 or 1 (65%),
  • PS 2 (29%),
  • PS 3 (5%) and
  • two or more prior therapies (51%).
• Study 4 was a randomized, multicenter, open-label trial in which 1466 patients were randomized to receive second-line treatment for metastatic NSCLC; 729 patients received Iressa 250 mg daily and 715 patients received docetaxel. The median duration of treatment with Iressa was 2.4 months.
• The study population characteristics were:
  • median age 61 years,
  • age less than 65 years (61%),
  • female (36%),
  • Caucasian (79%),
  • Asian (21%),
  • NSCLC adenocarcinoma histology (54%),
  • never smoker (20%),
  • ECOG PS 0 or 1 (88%) and
  • two or more prior therapies (16%).
• The pooled safety database from the three randomized trials was used to evaluate for serious and uncommon adverse drug reactions.
• Common adverse reactions were evaluated in Study 3.
• The most frequent adverse reactions in Study 3 (incidence of >20% and greater than placebo) reported in Iressa-treated patients were
  • skin reactions (47%) and
  • diarrhea (29%).
• The most frequent fatal adverse reactions in Iressa-treated patients were
  • respiratory failure (0.9%),
  • pneumonia (0.8%), and
  • pulmonary embolism (0.5%).
• Approximately 5% of Iressa-treated patients and 2.3% of placebo-treated patients discontinued treatment due to an adverse event.
• The most frequent adverse reactions that led to discontinuation in patients treated with Iressa were
  • nausea (0.5%),
  • vomiting (0.5%) and
  •  diarrhea (0.4%).

Table 1- Selected Adverse Drug Reactions Occurring with an Incidence Rate ≥5% and an Increase of >2% of Iressa-treated Patients in Study 3

Table 2 – Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Iressa- Treated Patients in Study 3

The following adverse reactions have been reported with Iressa across NSCLC trials (Study 2, Study 3 and Study 4) and are not listed elsewhere in Section 6:

• nausea (18%),
• asthenia (17%),
•  pyrexia (9%),
• alopecia (4.7%),
• hemorrhage (including epistaxis and hematuria) (4.3%),
• dry mouth (2%),
• dehydration (1.8%),
• allergic reactions including angioedema and urticaria (1.1%),
• elevations in blood creatinine (1.5%), and
• pancreatitis (0.1%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Iressa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Renal and urinary disorders: cystitis, hemorrhagic cystitis
• Skin and subcutaneous tissue disorders: cutaneous vasculitis

Drugs Affecting Gefitinib Exposure

CYP3A4 Inducer

• Drugs that are strong inducers of CYP3A4 increase the metabolism of gefitinib and decrease gefitinib plasma concentrations.
• Increase Iressa to 500 mg daily in patients receiving a strong CYP3A4 inducer (e.g., rifampicin, phenytoin, or tricyclic antidepressant) and resume Iressa at 250 mg 7 days after discontinuation of the strong inducer.

CYP3A4 Inhibitor

• Drugs that are strong inhibitors of CYP3A4 (e.g., ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations.
• Monitor adverse reactions when administering strong CYP3A4 inhibitors with Iressa.

Drugs Affecting Gastric pH

• Drugs that elevate gastric pH (e.g., proton pump inhibitors, histamine H₂-receptor antagonists, and antacids) may reduce plasma concentrations of gefitinib.
• Avoid concomitant use of Iressa with proton pump inhibitors, if possible.
• If treatment with a proton-pump inhibitor is required, take Iressa 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor.
• Take Iressa 6 hours after or 6 hours before an H₂-receptor antagonist or an antacid.

Hemorrhage In Patients Taking Warfarin

• International Normalized Ratio (INR) elevations and/or hemorrhage have been reported in some patients taking warfarin while on Iressa therapy.
• Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.