ADVERSE REACTIONS
The safety database includes 941 patients from clinical trials and approximately 23,000 patients in the Expanded Access Program.
Table 3 includes drug-related adverse events with an incidence of > 5% for the 216 patients who received either 250 mg or 500 mg of IRESSA monotherapy for treatment of NSCLC. The most common adverse events reported at the recommended 250 mg daily dose were diarrhea, rash, acne, dry skin, nausea, and vomiting (see PRECAUTIONS-Information for Patients and DOSAGE AND ADMINISTRATION−Dosage Adjustment sections). The 500 mg dose showed a higher rate for most of these adverse events.
Table 4 provides drug-related adverse events with an incidence of > 5% by CTC grade for the patients who received the 250 mg/day dose of IRESSA monotherapy for treatment of NSCLC. In clinical trials, 2–3% of patients stopped therapy due to an adverse drug reaction (ADR). The onset of these ADRs occurred within the first month of therapy.
Table 3: Drug-Related Adverse Events with an Incidence of ≥5% in either 250 mg or 500 mg Dose Group |
Number (%) of Patients
|
|
Drug-related adverse eventA patient may have had more than 1 drug-related event.
|
250 mg/day
(N=102)
%
|
500 mg/day
(N=114)
%
|
|
Diarrhea
|
49 (48)
|
76 (67)
|
|
Rash
|
44 (43)
|
61 (54)
|
|
Acne
|
25 (25)
|
37 (33)
|
|
Dry skin
|
13 (13)
|
30 (26)
|
|
Nausea
|
13 (13)
|
20 (18)
|
|
Vomiting
|
12 (12)
|
10 (9)
|
|
Pruritus
|
8 (8)
|
10 (9)
|
|
Anorexia
|
7 (7)
|
11 (10)
|
|
Asthenia
|
6 (6)
|
5 (4)
|
|
Weight loss
|
3 (3)
|
6 (5)
|
Table 4: Drug Related Adverse Events ≥5% at 250 mg dose by Worst CTC Grade (n=102) |
% of Patients
|
|
Adverse Event
|
All
Grades
|
CTC
Grade 1
|
CTC
Grade 2
|
CTC
Grade 3
|
CTC
Grade 4
|
|
Diarrhea
|
48
|
41
|
6
|
1
|
0
|
|
Rash
|
43
|
39
|
4
|
0
|
0
|
|
Acne
|
25
|
19
|
6
|
0
|
0
|
|
Dry Skin
|
13
|
12
|
1
|
0
|
0
|
|
Nausea
|
13
|
7
|
5
|
1
|
0
|
|
Vomiting
|
12
|
9
|
2
|
1
|
0
|
|
Pruritus
|
8
|
7
|
1
|
0
|
0
|
|
Anorexia
|
7
|
3
|
4
|
0
|
0
|
|
Asthenia
|
6
|
2
|
2
|
1
|
1
|
Other adverse events reported at an incidence of <5% in patients who received either 250 mg or 500 mg as monotherapy for treatment of NSCLC (along with their frequency at the 250 mg recommended dose) include the following: peripheral edema (2%), amblyopia (2%), dyspnea (2%), conjunctivitis (1%), vesiculobullous rash (1%), and mouth ulceration (1%).
Interstitial Lung Disease
Cases of interstitial lung disease (ILD) have been observed in patients receiving IRESSA at an overall incidence of about 1%. Approximately 1/3 of the cases have been fatal.
Based on data from worldwide clinical studies, expanded access/compassionate use and post-marketing use the estimated reporting rate of ILD-type events overall is approximately 0.3% outside of Japan and approximately 3% in Japan. From a phase III double blind clinical trial (1692 patients) comparing IRESSA plus best supportive care (BSC) to placebo plus BSC in patients with advanced NSCLC who had received 1 or 2 prior chemotherapy regimens and were refractory or intolerant to their most recent regimen, the incidence of ILD-type events in the overall population was similar, and approximately 1% in both treatment arms. The majority of ILD-type events reported were from patients of Asian ethnicity and the ILD incidence among patients of Asian ethnicity receiving IRESSA therapy and placebo was similar, approximately 3% and 4% respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo.
In a Post-Marketing Surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving IRESSA was 5.8%.
Reports have described the adverse event as interstitial pneumonia, pneumonitis and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. ILD has occurred in patients who have received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no previous therapy (12% of reported cases). Patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving IRESSA have been observed to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis.
In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), IRESSA therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately (see WARNINGS-Pulmonary Toxicity, PRECAUTIONS-Information for Patients and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
In patients receiving IRESSA therapy, there were reports of eye pain and corneal erosion/ulcer, sometimes in association with aberrant eyelash growth (see PRECAUTIONS-Information for Patients section). There have been reports of dry eyes, blepharitis and dry mouth, predominately mild in nature. Hemorrhage, such as epistaxis and hematuria have been reported in patients receiving IRESSA. There were also rare reports of pancreatitis and very rare reports of corneal membrane sloughing, ocular ischemia/hemorrhage, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, and allergic reactions, including angioedema and urticaria.
International Normalized Ratio (INR) elevations and/or bleeding events 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 (see CLINICAL PHARMACOLOGY-Drug-Drug Interactions and PRECAUTIONS-Drug Interactions sections).
Asymptomatic elevations in blood creatinine have been reported.
Data from non-clinical (in vitro and in vivo) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarization process (eg, QT interval). The clinical relevance of these findings is unknown.
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