TAGRISSO SIDE EFFECTS
- Generic Name: osimertinib tablets
- Brand Name: Tagrisso
- Drug Class: How Do Antineoplastic EGFR Inhibitors Work?
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Interstitial Lung Disease/Pneumonitis
- QTc Interval Prolongation
- Cardiomyopathy
- Keratitis
- Erythema multiforme and Stevens-Johnson syndrome
- Cutaneous Vasculitis
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 data in the Warnings and Precautions section reflect exposure to TAGRISSO in 1479 patients with EGFR mutation-positive NSCLC who received TAGRISSO at the recommended dose of 80 mg once daily in three randomized, controlled trials [ADAURA (n=337), FLAURA (n=279), and AURA3 (n=279)], two single arm trials [AURA Extension (n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173). Among 1479 patients who received TAGRISSO, 81% were exposed for 6 months or longer and 60% were exposed for greater than one year. In this pooled safety population, the most common adverse reactions in ≥20% of 1479 patients who received TAGRISSO were diarrhea (47%), rash (45%), musculoskeletal pain (36%), nail toxicity (33%), dry skin (32%), stomatitis (26%), fatigue (21%), and cough (20%). The most common laboratory abnormalities in ≥20% of 1479 patients who received TAGRISSO were leukopenia (65%), lymphopenia (62%), thrombocytopenia (53%), anemia (47%), and neutropenia (33%).
The data described below reflect exposure to TAGRISSO (80 mg daily) in 337 patients with EGFR mutation-positive resectable NSCLC, and 558 patients with EGFR mutation-positive metastatic NSCLC in three randomized, controlled trials [ADAURA (n=337), FLAURA (n=279), and AURA3 (n=279)]. Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies.
Adjuvant Treatment Of EGFR Mutation-Positive NSCLC
The safety of TAGRISSO was evaluated in ADAURA, a randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. At time of DFS analysis, the median duration of exposure to TAGRISSO was 22.5 months.
Serious adverse reactions were reported in 16% of patients treated with TAGRISSO. The most common serious adverse reaction (≥1%) was pneumonia (1.5%). Adverse reactions leading to dose reductions occurred in 9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were diarrhea (4.5%), stomatitis (3.9%), nail toxicity (1.8%) and rash (1.8%). Adverse reactions leading to permanent discontinuation occurred in 11% of patients treated with TAGRISSO. The most frequent adverse reactions leading to discontinuation of TAGRISSO were interstitial lung disease (2.7%), and rash (1.2%).
Tables 1 and 2 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.
Table 1: Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURAββ
| Adverse Reaction | TAGRISSO (N=337) |
PLACEBO (N=343) |
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| All Grades (%) | Grade 3 or higher† (%) | All Grades (%) | Grade 3 or higher† (%) | |
| Gastrointestinal Disorders | ||||
| Diarrhea* | 47 | 2.4 | 20 | 0.3 |
| Stomatitis‡ | 32 | 1.8 | 7 | 0 |
| Abdominal Pain** | 12 | 0.3 | 7 | 0 |
| Skin Disorders | ||||
| Rash§ | 40 | 0.6 | 19 | 0 |
| Nail toxicity¶ | 37 | 0.9 | 3.8 | 0 |
| Dry skin §§ | 29 | 0.3 | 7 | 0 |
| Pruritus# | 19 | 0 | 9 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| CoughÞ | 19 | 0 | 19 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Musculoskeletal Pain†† | 18 | 0.3 | 25 | 0.3 |
| Infection and Infestation Disorders | ||||
| Nasopharyngitis | 14 | 0 | 10 | 0 |
| Upper respiratory tract infection | 13 | 0.6 | 10 | 0 |
| Urinary Tract Infection¶¶ | 10 | 0.3 | 7 | 0 |
| General Disorders and Administration Site Conditions | ||||
| Fatigueβ | 13 | 0.6 | 9 | 0.3 |
| Nervous System Disorders | ||||
| Dizziness ## | 10 | 0 | 9 | 0 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 13 | 0.6 | 3.8 | 0 |
| ββNCI CTCAE v4.0. †All events were grade 3. *Includes diarrhea, colitis, enterocolitis, enteritis. ‡Includes aphthous ulcer, cheilitis, gingival ulceration, glossitis, tongue ulceration, stomatitis and mouth ulceration. **Includes abdominal discomfort, abdominal pain, abdominal lower pain, abdominal upper pain, epigastric discomfort, hepatic pain. §Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, eczema asteatotic, lichen planus, skin erosion, pustule. ¶Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. §§Includes dry skin, skin fissures, xerosis, eczema, xeroderma. #Includes pruritus, pruritus generalized, eyelid pruritus.þIncludes cough, productive cough, upper-airway cough syndrome ††Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck |
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Table 2: Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in ADAURA
| Laboratory Abnormality*,† | TAGRISSO (N=337) |
PLACEBO (N=343) |
||
| All Grades (%) | Grade 3 or Grade 4 (%) | All Grades (%) | Grade 3 or Grade 4 (%) | |
| Hematology | ||||
| Leukopenia | 54 | 0 | 25 | 0 |
| Thrombocytopenia | 47 | 0 | 7 | 0.3 |
| Lymphopenia | 44 | 3.4 | 14 | 0.9 |
| Anemia | 30 | 0 | 12 | 0.3 |
| Neutropenia | 26 | 0.6 | 10 | 0.3 |
| Chemistry | ||||
| Hyperglycemia | 25 | 2.3 | 30 | 0.9 |
| Hypermagnesemia | 24 | 1.3 | 14 | 1.5 |
| Hyponatremia | 20 | 1.8 | 16 | 1.5 |
| *NCI CTCAE v4.0 †Based on the number of patients with available follow-up laboratory data |
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Laboratory abnormalities in ADAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (10%).
Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer
The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months.
Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%).
Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA.
Table 3: Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA*
| Adverse Reaction | TAGRISSO (N=279) |
EGFR TKI comparator (gefitinib or erlotinib) (N=277) |
||
| Any Grade (%) | Grade 3 or higher (%) | Any Grade (%) | Grade 3 or higher (%) | |
| Gastrointestinal Disorders | ||||
| Diarrhea† | 58 | 2.2 | 57 | 2.5 |
| Stomatitis|| | 32 | 0.7 | 22 | 1.1 |
| Nausea | 14 | 0 | 19 | 0 |
| Constipation | 15 | 0 | 13 | 0 |
| Vomiting | 11 | 0 | 11 | 1.4 |
| Skin Disorders | ||||
| Rash* | 58 | 1.1 | 78 | 7 |
| Dry skin§ | 36 | 0.4 | 36 | 1.1 |
| Nail toxicity¶ | 35 | 0.4 | 33 | 0.7 |
| Pruritus# | 17 | 0.4 | 17 | 0 |
| General Disorders and Administration Site Conditions | ||||
| FatigueÞ | 21 | 1.4 | 15 | 1.4 |
| Pyrexia | 10 | 0 | 4 | 0.4 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 20 | 2.5 | 19 | 1.8 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 17 | 0 | 15 | 0.4 |
| Dyspnea | 13 | 0.4 | 7 | 1.4 |
| Neurologic Disorders | ||||
| Headache | 12 | 0.4 | 7 | 0 |
| Cardiac Disorders | ||||
| Prolonged QT Intervalβ | 10 | 2.2 | 4 | 0.7 |
| Infection and Infestation Disorders | ||||
| Upper Respiratory Tract Infection | 10 | 0 | 7 | 0 |
| *NCI CTCAE v4.0 †One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator. ||Includes stomatitis and mouth ulceration. ‡Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule. §Includes dry skin, skin fissures, xerosis, eczema, xeroderma. ¶Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. #Includes pruritus, pruritus generalized, eyelid pruritus. þIncludes fatigue, asthenia. β Includes prolonged QT interval reported as adverse reaction. |
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Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), palmar-plantar erythrodysaesthesia syndrome (1.4%), QTc interval prolongation (1.1%), and keratitis (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.
Table 4: Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA
| Laboratory Abnormality*† | TAGRISSO (N=279) |
EGFR TKI comparator (gefitinib or erlotinib) (N=277) |
||
| All Grades (%) | Grade 3 or Grade 4 (%) | All Grades (%) | Grade 3 or Grade 4 (%) | |
| Hematology | ||||
| Lymphopenia | 63 | 6 | 36 | 4.2 |
| Anemia | 59 | 0.7 | 47 | 0.4 |
| Thrombocytopenia | 51 | 0.7 | 12 | 0.4 |
| Neutropenia | 41 | 3 | 10 | 0 |
| Chemistry | ||||
| Hyperglycemia‡ | 37 | 0 | 31 | 0.5 |
| Hypermagnesemia | 30 | 0.7 | 11 | 0.4 |
| Hyponatremia | 26 | 1.1 | 27 | 1.5 |
| Increased AST | 22 | 1.1 | 43 | 4.1 |
| Increased ALT | 21 | 0.7 | 52 | 8 |
| Hypokalemia | 16 | 0.4 | 22 | 1.1 |
| Hyperbilirubinemia | 14 | 0 | 29 | 1.1 |
| *NCI CTCAE v4.0 †Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: 267 -273 and EGFR TKI comparator range: 256 -268) ‡Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191) |
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Clinically relevant laboratory abnormalities in FLAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (9%).
Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer
The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).
Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).
Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).
Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3.
Table 5: Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3*
| Adverse Reaction | TAGRISSO (N=279) |
Chemotherapy (Pemetrexed/ Cisplatin or Pemetrexed/ Carboplatin) (N=136) |
||
| All Grades†(%) | Grade 3/4† (%) | All Grades† (%) | Grade 3/4† (%) | |
| Gastrointestinal Disorders | ||||
| Diarrhea | 41 | 1.1 | 11 | 1.5 |
| Nausea | 16 | 0.7 | 49 | 3.7 |
| Stomatitis|| | 19 | 0 | 15 | 1.5 |
| Constipation | 14 | 0 | 35 | 0 |
| Vomiting | 11 | 0.4 | 20 | 2.2 |
| Skin Disorders | ||||
| Rash‡ | 34 | 0.7 | 6 | 0 |
| Dry skin§ | 23 | 0 | 4.4 | 0 |
| Nail toxicity¶ | 22 | 0 | 1.5 | 0 |
| Pruritus# | 13 | 0 | 5 | 0 |
| General Disorders and Administration Site Conditions | ||||
| FatigueÞ | 22 | 1.8 | 40 | 5.1 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 18 | 1.1 | 36 | 2.9 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 17 | 0 | 14 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Back pain | 10 | 0.4 | 9 | 0.7 |
| *NCI CTCAE v4.0. †No grade 4 events were reported. ||Includes stomatitis and mouth ulceration ‡Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis, acneiform dermatitis, pustule. § Includes dry skin, eczema, skin fissures, xerosis. ¶Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia. #Includes pruritus, pruritus generalized, eyelid pruritus. ÞIncludes fatigue, asthenia. |
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Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), palmar-plantar erythrodysaesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%), and erythema multiform (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.
Table 6: Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3
| Laboratory Abnormality*,† | TAGRISSO (N=279) |
Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=131) |
||
| All Grades (%) | Grade 3 or Grade 4 (%) | All Grades (%) | Grade 3 or Grade 4 (%) | |
| Hematology | ||||
| Anemia | 43 | 0 | 79 | 3.1 |
| Lymphopenia | 63 | 8 | 61 | 10 |
| Thrombocytopenia | 46 | 0.7 | 48 | 7 |
| Neutropenia | 27 | 2.2 | 49 | 12 |
| Chemistry | ||||
| Hypermagnesemia† | 27 | 1.8 | 9 | 1.5 |
| Hyponatremia† | 26 | 2.2 | 36 | 1.5 |
| Hyperglycemia‡ | 20 | 0 | NA | NA |
| Hypokalemia† | 9 | 1.4 | 18 | 1.5 |
| NA=not applicable *NCI CTCAE v4.0 †Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 279, Chemotherapy comparator 131) ‡Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 270, Chemotherapy 5; fasting glucose was not a protocol requirement for patients in the chemotherapy arm) |
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Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%).
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of TAGRISSO. 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.
Skin and subcutaneous tissue: Stevens-Johnson syndrome, erythema multiforme, cutaneous vasculitis.
SRC: NLM .