TAGRISSO (Page 2 of 8)

3 DOSAGE FORMS AND STRENGTHS

80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse.

40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease/Pneumonitis

Interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of the 1479 TAGRISSO-treated patients; 0.3% of cases were fatal.

Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6)].

5.2 QTc Interval Prolongation

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1479 patients treated with TAGRISSO in clinical trials, 0.8% were found to have a QTc > 500 msec, and 3.1% of patients had an increase from baseline QTc > 60 msec [see Clinical Pharmacology (12.2)]. No QTc-related arrhythmias were reported.

Clinical trials of TAGRISSO did not enroll patients with baseline QTc of > 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.4)].

5.3 Cardiomyopathy

Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 3% of the 1479 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal.

A decline in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and to less than 50% LVEF occurred in 3.2% of 1233 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.

Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.4)].

5.4 Keratitis

Keratitis was reported in 0.7% of 1479 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

5.5 Erythema Multiforme and Stevens-Johnson Syndrome

Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if SJS or EMM is suspected and permanently discontinue if confirmed.

5.6 Cutaneous Vasculitis

Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity.

5.7 Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

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

Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
QTc Interval Prolongation [see Warnings and Precautions (5.2)]
Cardiomyopathy [see Warnings and Precautions (5.3)]
Keratitis [see Warnings and Precautions (5.4)]
Erythema multiforme and Stevens-Johnson syndrome [see Warnings and Precautions (5.5)]
Cutaneous Vasculitis [see Warnings and Precautions (5.6)]

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 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) [see Warnings and Precautions (5)]. 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 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.

Table 2. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURA *
Adverse Reaction TAGRISSO(N=337) PLACEBO(N=343)
All Grades (%) Grade 3 or higher (%) All Grades (%) Grade 3 or higher (%)
*
NCI 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.
Þ
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.
ß
Includes dry skin, skin fissures, xerosis, eczema, xeroderma.
à
Includes pruritus, pruritus generalized, eyelid pruritus.
è
Includes cough, productive cough, upper-airway cough syndrome
ð
Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.
ø
Includes cystitis, urinary tract infection, and urinary tract infection bacterial.
ý
Includes asthenia, fatigue
£
Includes dizziness, vertigo, and vertigo positional.

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 Þ

37

0.9

3.8

0

Dry skin ß

29

0.3

7

0

Pruritus à

19

0

9

0

Respiratory, Thoracic and Mediastinal Disorders

Cough è

19

0

19

0

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal Pain ð

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 ø

10

0.3

7

0

General Disorders and Administration Site Conditions

Fatigue ý

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

Clinically relevant adverse reactions in ADAURA in <10% of patients receiving TAGRISSO were alopecia (6%), epistaxis (6%), interstitial lung disease (3%), palmar-plantar erythrodysesthesia syndrome (1.8%), urticaria (1.5%), keratitis (0.6%), QTc interval prolongation (0.6%), and erythema multiform (0.3%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.

Table 3. 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 (%)
*
NCI CTCAE v4.0
Based on the number of patients with available follow-up laboratory data

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

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 4 and 5 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA.

Table 4. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA *
*
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.
Þ
Includes pruritus, pruritus generalized, eyelid pruritus.
ß
Includes fatigue, asthenia.
à
Includes prolonged QT interval reported as adverse reaction.

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 Þ

17

0.4

17

0

General Disorders and Administration Site Conditions

Fatigue ß

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 Interval à

10

2.2

4

0.7

Infection and Infestation Disorders

Upper Respiratory Tract Infection

10

0

7

0

Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), urticaria (2.2%), palmar-plantar erythrodysesthesia 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 5. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA
*
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)

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

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 6 and 7 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3.

Table 6. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3*
*
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.
Þ
Includes pruritus, pruritus generalized, eyelid pruritus.
ß
Includes fatigue, asthenia.

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 Þ

13

0

5

0

General Disorders and Administration Site Conditions

Fatigue ß

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

Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), urticaria (2.9%), palmar-plantar erythrodysesthesia 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 7. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3
*
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)

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

Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%).

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