Gefitinib
Generic: GEFITINIB
Basic Information
Manufacturer
Teva Pharmaceuticals, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
3dd135f0-5db1-4236-9756-04533b66dc9d
Indications & Usage
1 INDICATIONS AND USAGE Gefitinib tablets are indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Clinical Studies (14 ) ] .
Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations [see Clinical Studies (14) ] .
Gefitinib tablets are a tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
( 1 ) Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.
( 1 )
Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations [see Clinical Studies (14) ] .
Gefitinib tablets are a tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
( 1 ) Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.
( 1 )
Adverse Reactions
6 ADVERSE REACTIONS The following adverse drug reactions are discussed in more detail in other sections of the labeling: Interstitial Lung Disease [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Gastrointestinal Perforation [see Warnings and Precautions (5.3) ] Severe or Persistent Diarrhea [see Warnings and Precautions (5.4) ] Ocular Disorders including Keratitis [see Warnings and Precautions (5.5) ] Bullous and Exfoliative Skin Disorders [see Warning and Precautions (5.6) ] The most commonly reported adverse drug reactions (ADRs), reported in more than 20% of the patients and greater than placebo were skin reactions and diarrhea.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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 gefitinib tablets are based on the data from 2462 patients with NSCLC who received gefitinib tablets 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 gefitinib tablets 250 mg daily and 589 patients received carboplatin/paclitaxel.
The median duration of treatment with gefitinib tablets 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 gefitinib tablets 250 mg daily and 562 patients received placebo.
The median duration of treatment with gefitinib tablets 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 gefitinib tablets 250 mg daily and 715 patients received docetaxel.
The median duration of treatment with gefitinib tablets 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 greater than 20% and greater than placebo) reported in gefitinib tablets-treated patients were skin reactions (47%) and diarrhea (29%).
The most frequent fatal adverse reactions in gefitinib tablets-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%).
Approximately 5% of gefitinib tablets-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 gefitinib tablets 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 Gefitinib Tablets-Treated Patients in Study 3 Adverse Reaction Percentage (%) of patients Gefitinib Tablets (N=1126) Placebo (N=562) All Grades Grade 3 and 4 All Grades Grade 3 and 4 Skin and subcutaneous tissue disorders Skin reactions 1 47% 2% 17% 0.4% Nail disorders 2 5% 0.1% 0.7% 0% Gastrointestinal disorders Diarrhea 3 29% 3% 10% 1% Vomiting 14% 1.2% 10% 0.4% Stomatitis 4 7% 0.3% 4% 0.2% Metabolism and nutrition disorders Decreased appetite 17% 2.3% 14% 2.0% Eye disorders Conjunctivitis/blepharitis/ dry eye 5 6% 0% 3.2% 0% 1 Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drug eruption, Dry skin, Erythema, Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma 2 Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 3 Includes Diarrhea, Feces soft, Frequent bowel movements 4 Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration 5 Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus Table 2 – Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Gefitinib Tablets-Treated Patients in Study 3 Gefitinib T ablets Placebo Adverse Reaction All Grades % Grade 3 and 4 % All Grades % Grade 3 and 4 % Alanine aminotransferase increased 1 38% 2 2.4% 23% 2 1.4% 4 Aspartate aminotransferase increased 1 40% 3 2.0% 25% 3 1.3% 5 Proteinuria 35% 4.7% 31% 3.3% 1 Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 2 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 3 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 4 0.2% of placebo patients were CTC grade 3 at baseline 5 0.4% of placebo patients were CTC grade 3 at baseline The following adverse reactions have been reported with gefitinib tablets 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%), elevations in blood creatinine (1.5%), allergic reactions including angioedema and urticaria (1.1%), palmar-plantar erythrodysesthesia syndrome (0.2%) and pancreatitis (0.1%).
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of gefitinib tablets.
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
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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 gefitinib tablets are based on the data from 2462 patients with NSCLC who received gefitinib tablets 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 gefitinib tablets 250 mg daily and 589 patients received carboplatin/paclitaxel.
The median duration of treatment with gefitinib tablets 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 gefitinib tablets 250 mg daily and 562 patients received placebo.
The median duration of treatment with gefitinib tablets 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 gefitinib tablets 250 mg daily and 715 patients received docetaxel.
The median duration of treatment with gefitinib tablets 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 greater than 20% and greater than placebo) reported in gefitinib tablets-treated patients were skin reactions (47%) and diarrhea (29%).
The most frequent fatal adverse reactions in gefitinib tablets-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%).
Approximately 5% of gefitinib tablets-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 gefitinib tablets 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 Gefitinib Tablets-Treated Patients in Study 3 Adverse Reaction Percentage (%) of patients Gefitinib Tablets (N=1126) Placebo (N=562) All Grades Grade 3 and 4 All Grades Grade 3 and 4 Skin and subcutaneous tissue disorders Skin reactions 1 47% 2% 17% 0.4% Nail disorders 2 5% 0.1% 0.7% 0% Gastrointestinal disorders Diarrhea 3 29% 3% 10% 1% Vomiting 14% 1.2% 10% 0.4% Stomatitis 4 7% 0.3% 4% 0.2% Metabolism and nutrition disorders Decreased appetite 17% 2.3% 14% 2.0% Eye disorders Conjunctivitis/blepharitis/ dry eye 5 6% 0% 3.2% 0% 1 Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drug eruption, Dry skin, Erythema, Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma 2 Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 3 Includes Diarrhea, Feces soft, Frequent bowel movements 4 Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration 5 Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus Table 2 – Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Gefitinib Tablets-Treated Patients in Study 3 Gefitinib T ablets Placebo Adverse Reaction All Grades % Grade 3 and 4 % All Grades % Grade 3 and 4 % Alanine aminotransferase increased 1 38% 2 2.4% 23% 2 1.4% 4 Aspartate aminotransferase increased 1 40% 3 2.0% 25% 3 1.3% 5 Proteinuria 35% 4.7% 31% 3.3% 1 Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 2 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 3 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 4 0.2% of placebo patients were CTC grade 3 at baseline 5 0.4% of placebo patients were CTC grade 3 at baseline The following adverse reactions have been reported with gefitinib tablets 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%), elevations in blood creatinine (1.5%), allergic reactions including angioedema and urticaria (1.1%), palmar-plantar erythrodysesthesia syndrome (0.2%) and pancreatitis (0.1%).
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of gefitinib tablets.
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