Adverse reactions : תופעות לוואי

6   ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
•   Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)].
•   Infusion-Related Reactions [see Warnings and Precautions (5.2)].


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 described in the Warnings and Precautions section reflect exposure to IMFINZI as a single agent in a total of 1889 patients enrolled in the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumors), and an additional open-label, single-arm trial (ATLANTIC Study) that enrolled 444 patients with advanced solid tumors, including NSCLC. In these trials, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more.


The data also reflect exposure to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC), in 338 patients from the TOPAZ-1 study (a randomized, double-blind study in patients with BTC). In the CASPIAN and TOPAZ-1 studies, IMFINZI was administered at a dose of 1,500 mg every 3 or 4 weeks.


The data described in the Warnings and Precautions also reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab 300 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMFINZI 1,500 mg in combination with tremelimumab as a single intravenous infusion of 300 mg, followed by IMFINZI 1,500 mg every 4 weeks. The pooled safety population (N=596) described in the Warnings and Precautions section reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab 75 mg and histology-based platinum chemotherapy regimens in 330 patients in POSEIDON [see Clinical Studies (14.2)] and 266 patients with ES-SCLC in CASPIAN who received up to four cycles of platinum-etoposide plus IMFINZI 1,500 mg with tremelimumab 75 mg every 3 weeks followed by IMFINZI 1,500 mg every 4 weeks (an unapproved regimen for extensive stage small cell 
lung cancer). Among the 596 patients, 55% were exposed to IMFINZI for 6 months or more and 24% were exposed for 12 months or more.


The data described in this section reflect exposure to IMFINZI in patients with Stage III NSCLC enrolled in the PACIFIC study, in patients with metastatic NSCLC enrolled in the POSEIDON study, in patients with ES-SCLC enrolled in the CASPIAN study, in patients with BTC enrolled in the TOPAZ-1 study and in patients with uHCC included in the HIMALAYA study.


Urothelial Carcinoma
The safety of IMFINZI was evaluated in 182 patients with locally advanced or metastatic urothelial carcinoma in the urothelial carcinoma cohort of Study 1108 whose disease has progressed during or after one standard platinum-based regimen. Patients received 10 mg/kg intravenously every 2 weeks [see Clinical Studies (14.1)]. The median duration of exposure was 2.3 months (range: 1 day to 12.1 months).


Thirty-one percent (31%) of patients had a drug delay or interruption for an adverse reaction. The most common (>2%) were liver injury (4.9%), urinary tract infection (3.3%), acute kidney injury (3.3%), and musculoskeletal pain (2.7%).


The most common adverse reactions (≥15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%) and urinary tract infection (15%).
The most common Grade 3 or 4 adverse reactions (≥3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration.


Eight patients (4.4%) who were treated with IMFINZI experienced Grade 5 adverse events of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune- mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. IMFINZI was discontinued for adverse reactions in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (>2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, pyrexia/tumor associated fever 
(2.7% each).

Table 5 summarizes the adverse reactions that occurred in ≥10% of patients, while Table 4 summarizes the Grade 3 - 4 laboratory abnormalities that occurred in ≥1% of patients treated with IMFINZI in the urothelial carcinoma cohort of Study 1108.


Table 5. Adverse Reactions in ≥10% of Patients in study 1108 Urothelial Carcinoma Cohort IMFINZI (N=182)
Adverse Reaction                                                      All Grades      Grades 3 – 4 (%) (%)
Gastrointestinal Disorders
Constipation                                                             21                 1.1 Nausea                                                                   16                 1.6 Abdominal pain1                                                          14                 2.7 Diarrhea/Colitis                                                         13                 1.1 General Disorders and Administration
Fatigue2                                                                 39                  6 Peripheral edema3                                                        15                 1.6 Pyrexia/Tumor associated fever                                           14                 0.5 Infections
Urinary tract infection4                                                 15                 4.4 Metabolism and Nutrition Disorders
Decreased appetite/Hypophagia                                            19                 0.5 Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain5                                                    24                 3.8 Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea/Exertional Dyspnea                                               13                 2.2 Cough/Productive Cough                                                   10                  0 Skin and Subcutaneous Tissue Disorders
Rash6                                                                    11                 0.5 1 Includes abdominal pain upper, abdominal pain lower and flank pain

2 Includes asthenia, lethargy, and malaise
3 Includes edema, localized edema, edema peripheral, lymphedema, peripheral swelling, scrotal edema, and scrotal swelling 4 Includes cystitis, candiduria and urosepsis
5 Includes back pain, musculoskeletal chest pain, musculoskeletal pain and discomfort, myalgia, and neck pain 6 Includes dermatitis, dermatitis acneiform, dermatitis psoriasiform, psoriasis, rash maculo-papular, rash pruritic, rash papular, rash pustular, skin toxicity, eczema, erythema, erythema multiforme, rash erythematous, acne, and lichen planus 

Table 6. Grade 3-4 Laboratory Abnormalities Worsened from Baseline Occurring in ≥1% Patients in Study 1108 Urothelial Carcinoma Cohort
Laboratory Abnormality                                           Grade 3 – 4 % 
Hyponatremia                                                    12
Lymphopenia                                                     11
Anemia                                                       8
Increased alkaline phosphatase                                              4.1 Hypermagnesemia                                                    4.2 Hypercalcemia                                                     3
Hyperglycemia                                                     3
Increased AST                                                    2.4
Increased ALT                                                   0.6
Hyperbilirubinemia                                                 1.2 Increased creatinine                                                1.2 Neutropenia                                                    1.2
Hyperkalemia                                                    1.2
Hypokalemia                                                    1.2
Hypoalbuminemia                                                    1.2 

Non-Small Cell Lung Cancer
Stage III NSCLC - PACIFIC
The safety of IMFINZI in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received IMFINZI 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression. [see Clinical Studies (14.2)].
The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to IMFINZI was 10 months (range: 0.2 to 12.6).

IMFINZI was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to IMFINZI discontinuation were pneumonitis or radiation pneumonitis in 6% of patients.
Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea and rash.


Table 7 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI.
Table 7. Adverse Reactions Occurring in ≥ 10% Patients in the PACIFIC Study 
IMFINZI                                 Placebo
N=475                                      N=234
Adverse Reaction                          All Grades Grades 3-4 (%) All Grades (%) Grades (%)                                           3-4 (%)

Respiratory, Thoracic and Mediastinal Disorders

Cough/Productive Cough                        40             0.6              30             0.4 

Pneumonitis2/Radiation Pneumonitis            34             3.4              25             3 

Dyspnea3                                      25             1.5              25             2.6 
Gastrointestinal Disorders

Diarrhea                                                         18                   0.6                    19                 1.3 
Abdominal pain4                                                  10                   0.4                     6                 0.4 
Endocrine Disorders

Hypothyroidism5                                                  12                   0.2                    1.7                 0 
Skin and Subcutaneous Tissue Disorders

Rash6                                                            23                   0.6                    12                  0 
Pruritus7                                                        12                    0                      6                  0 
General Disorders

Fatigue8                                                         34                   0.8                    32                 1.3 
Pyrexia                                                          15                   0.2                     9                  0 
Infections

Upper respiratory tract                                          26                   0.4                    19                  0 infections9
Pneumonia10                                                      17                    7                     12                  6 

2   includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, pulmonary fibrosis
3   includes dyspnea and exertional dyspnea
4   includes abdominal pain, abdominal pain lower, abdominal pain upper, and flank pain
5 includes autoimmune hypothyroidism and hypothyroidism
6 includes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash and dermatitis
7 includes pruritus generalized and pruritus
8 includes asthenia and fatigue

9 includes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis, and upper respiratory tract infection
10 includes lung infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia klebsiella, pneumonia necrotising, pneumonia pneumococcal, and pneumonia streptococcal 


Other adverse reactions occurring in less than 10% of patients treated with IMFINZI were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections.
Table 8 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI.


Table 8. Laboratory Abnormalities Worsening From Baseline Occurring in ≥ 20% of Patients in the PACIFIC Study

IMFINZI                               Placeb o

Laboratory Abnormality                                         Grade 3 or                         Grade 3 or All                                   All
4 (%)                              4 (%)
Grades1                              Grades1

(%)2                                  (%)2

Chemistry
Hyperglycemia                                     52                  8                51                8 Hypocalcemia                                      46                 0.2               41                0 Increased ALT                                     39                 2.3               22              0.4 Increased AST                                     36                 2.8               21              0.4 Hyponatremia                                      33                 3.6               30              3.1 Hyperkalemia                                      32                 1.1               29              1.8 Increased GGT                                     24                 3.4               22              1.7 Hematology
Lymphopenia                                       43                 17                39               18 1
Graded according to NCI CTCAE version 4.0
2
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 464 to 470) and placebo (range: 224 to 228)
Metastatic NSCLC - POSEIDON
The safety of IMFINZI in combination with tremelimumab and platinum-based chemotherapy in patients with metastatic NSCLC was evaluated in POSEIDON (NCT03164616), a randomized, open-label, multicenter, active-controlled trial. A total of 330 patients received IMFINZI 1,500 mg in combination with tremelimumab (≥ 30 kg body weight received 75 mg and < 30 kg body weight received 1 mg/kg) and histology-based platinum chemotherapy regimens [see Clinical Studies (14.2)]. Of these patients, 66% received the maximum 5 doses of tremelimumab and 79% received at least 4 doses. Treatment was continued with IMFINZI as a single agent (or with IMFINZI and histologically-based pemetrexed for non-squamous patients based on the investigator’s decision) until disease progression or unacceptable toxicity. The trial excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.2)].


The median age of patients who received IMFINZI in combination with tremelimumab and platinum-based chemotherapy was 63 years (range: 27 to 87); 80% male; 61% White, 29% Asian, 58% former smoker, 25% current smoker, and 68% ECOG performance of 1.


Serious adverse reactions occurred in 44% of patients receiving IMFINZI in combination with tremelimumab and platinum-based chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in a total of 4.2% of patients receiving IMFINZI in combination with tremelimumab and platinum-based chemotherapy. These include hepatitis, nephritis, myocarditis, pancreatitis (all in the same patient), death (2 patients), sepsis (2 patients), pneumonitis (2 patients), acute kidney injury (2 patients), febrile neutropenia (1 patient), chronic obstructive pulmonary disease (1 patient), dyspnea (1 patient), sudden death (1 patient), and ischemic stroke (1 patient).


Permanent discontinuation of IMFINZI or tremelimumab due to an adverse reaction occurred in 17% of the patients.
Adverse reactions which resulted in permanent discontinuation of IMFINZI or tremelimumab in > 2% of patients included pneumonia.


Dosage interruption or delay of IMFINZI and tremelimumab due to an adverse reaction occurred in 41% of patients.
Adverse reactions which required dosage interruption or delay of IMFINZI and tremelimumab in > 1% of patients included anemia, leukopenia/white blood cell count decreased, pneumonia, pneumonitis, colitis, diarrhea, hepatitis, rash, asthenia, amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, neutropenia/neutrophil count decreased, and thrombocytopenia/platelet count decreased.


The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities (≥ 10%) were neutropenia, anemia, leukopenia, lymphocytopenia, lipase increased, hyponatremia and thrombocytopenia.

Table 9 summarizes the adverse reactions in POSEIDON.

Table 9. Adverse Reactions ( ≥ 10%) in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study IMFINZI with tremelimumab and
Platinum-based chemotherapy platinum-based chemotherapy
N = 333
N = 330
Adverse Reaction               All Grades (%)        Grade 3 or 4 (%)        All Grades (%)          Grade 3 or 4 (%)
Respiratory, thoracic and mediastinal disorders
IMFINZI with tremelimumab and
Platinum-based chemotherapy platinum-based chemotherapy
N = 333
N = 330
Adverse Reaction           All Grades (%)         Grade 3 or 4 (%)         All Grades (%)         Grade 3 or 4 (%)
Cough/Productive Cough*                   12                      0                       8                    0.3 Gastrointestinal disorders
Nausea                                    42                     1.8                     37                    2.1 Diarrhea                                  22                     1.5                     15                    1.5 Constipation                              19                      0                      24                    0.6 Vomiting                                  18                     1.2                     14                    1.5 Stomatitis†                               10                      0                       6                    0.3 Endocrine disorders
Hypothyroidism‡                           13                      0                      2.1                    0 Skin and subcutaneous tissue disorders
Rash§                                     27                     2.4                     10                    0.6 Alopecia                                  10                      0                       6                     0 Pruritus                                  11                      0                      4.5                    0 General disorders and administration site conditions
Fatigue/Asthenia¶                         36                      5                      32                    4.5 Pyrexia#                                  19                      0                       8                     0 EdemaÞ                                    10                      0                      10                    0.6 Musculoskeletal and connective tissue disorders
Musculoskeletal Painß                     29                     0.6                     22                    1.5 Metabolism and nutrition disorders
Decreased appetite                        28                     1.5                     25                    1.2 Infections and Infestations
Pneumonia à                               17                      8                      12                    4.2 Upper respiratory tract                   15                     0.6                      9                    0.9 infectionsè
Nervous system disorders
Headacheð                                 11                      0                       8                    0.6 * Includescough and productive cough.
† Includes mucosal inflammation and stomatitis.
‡ Includes blood thyroid stimulating hormone increased and hypothyroidism.

§ Includes eczema, erythema, dermatitis, drug eruption, erythema multiforme, pemphigoid, rash, rash maculo-papular, rash papular, 

rash pruritic, and rash pustular.
¶ Includes asthenia and fatigue.
# Includes body temperature increased, hyperpyrexia, hyperthermia, and pyrexia.
Þ Includes face edema, localized edema, and edema peripheral.

ß Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-  cardiac chest pain, spinal pain.
à Includes lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, pneumonia  bacterial.
è Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection.

ð   Includes headache, migraine.


Table 10 summarizes the laboratory abnormalities in POSEIDON.


Table 10. Select Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study
Laboratory Abnormality*          IMFINZI with tremelimumab and                Platinum-based chemotherapy§ platinum-based chemotherapy†
All Grades           Grade 3 or 4            All Grades           Grade 3 or 4 (%)                   (%)                    (%)                   (%) Chemistry
Lipase increased                         35                    14                    25                     5 Hyponatremia                             55                    13                    50                    11 Hypernatremia                            15                     0                    14                     0 Amylase increased                        41                     9                    25                     6 Hypokalemia                              21                     7                    17                    2.8 Hyperglycemia                            42                     6                    37                    3.1 Increased ALT                            64                     6                    56                    4.7 Increased AST                            63                     5                    55                    2.2 Blood creatinine increased               89                    4.0                   83                    1.9 Increased Alkaline                       33                    3.4                   26                    1.2 Phosphatase
Gamma Glutamyl                           38                    2.2                   35                    4.7 Transferase increased
Hyperkalemia                             49                    2.2                   35                    2.8 Albumin decreased                        27                    1.9                   18                    0.9 Hypocalcemia                             58                    0.9                   49                    0.9 Hypomagnesemia                           12                     4                    23                     0 
Laboratory Abnormality*         IMFINZI with tremelimumab and           Platinum-based chemotherapy§ platinum-based chemotherapy†
All Grades         Grade 3 or 4         All Grades         Grade 3 or 4 (%)                 (%)                  (%)                 (%)
Bilirubinemia                          16                  0.9                  8                  0.3 Hematology
Neutropenia                            71                  37                  69                  32 Anemia                                 84                  24                  84                  25 Leukopenia                             77                  21                  81                  18 Lymphocytopenia                        67                  20                  60                  19 Thrombocytopenia                       53                  11                  54                  12 * Graded   according to NCI CTCAE version 4.03.
†   The denominator used to calculate the rate varied from 45 to 326 based on the number of patients with a baseline value and at least one post-treatment value.
§   The denominator used to calculate the rate varied from 43 to 323 based on the number of patients with a baseline value and at least one post-treatment value.


Small Cell Lung Cancer

Extensive Stage Small Cell Lung Cancer – CASPIAN

The safety of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was evaluated in CASPIAN, a randomized, open-label, multicenter, active-controlled trial. A total of 265 patients received IMFINZI 1,500 mg in combination with chemotherapy every 3 weeks for 4 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity. The trial excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.3)].


Among 265 patients receiving IMFINZI, 49% were exposed for 6 months or longer and 19% were exposed for 12 months or longer.


Among 266 patients receiving chemotherapy alone, 57% of the patients received 6 cycles of chemotherapy and 8% of the patients received prophylactic cranial irradiation (PCI) after chemotherapy.

IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. These include pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis and pancytopenia (1 patient each). Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. These include pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (1 patient each) and sudden death (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue/asthenia and alopecia.


Table 11 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy.


Table 11. Adverse Reactions Occurring in ≥ 10% of Patients in the CASPIAN study IMFINZI with etoposide and       Etoposide and either either carboplatin or cisplatin carboplatin or cisplatin N =
N = 265                          266

Adverse Reaction       All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Respiratory, thoracic and mediastinal disorders
Cough/Productive       15               0.8             9               0 Cough

Gastrointestinal disorders
Nausea                 34               0.4             34              1.9 Constipation           17               0.8             19              0 Vomiting               15               0               17              1.1 Diarrhea               10               1.1             11              1.1 Endocrine disorders

Hyperthyroidisma       10               0                0.4            0 

Skin and subcutaneous tissue disorders
Alopecia                 31               1.1                34          0.8 Rashb                    11               0                  6           0 General disorders and administration site conditions
Fatigue/Asthenia         32               3.4                32          2.3 Metabolism and nutrition disorders
Decreased appetite       18               0.8                17          0.8 

 a Includes   hyperthyroidism and Basedow's disease b Includes   rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash and dermatitis


Table 12 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy.


Table 12. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20%1 of Patients in the CASPIAN study


IMFINZI with         Etoposide and
Etoposide and either either Carboplatin
Carboplatin or       or Cisplatin

Cisplatin



Laboratory Abnormality                      Grade2 3 or 4 (%)3      Grade2 3 or 4 (%)3 
Chemistry
Hyponatremia                               11                       13 Hypomagnesemia                             11                       6 Hyperglycemia                              5                        5 Increased Alkaline Phosphatase             4.9                      3.5 Increased ALT                              4.9                      2.7 Increased AST                              4.6                      1.2 Hypocalcemia                               3.5                      2.4 Blood creatinine increased                 3.4                      1.1 Hyperkalemia                               1.5                      3.1 TSH decreased < LLN4 and ≥ LLN at          NA                       NA baseline

Hematology
Neutropenia                                41                       48 Lymphopenia                                14                       13 Anemia                                     13                       22 Thrombocytopenia                           12                       15 1 The   frequency cut off is based on any grade change from baseline
2 Graded   according to NCI CTCAE version 4.03
3 Each   test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 258 to 263) and chemotherapy (range: 253 to 262) except magnesium IMFINZI + chemotherapy(18) and chemotherapy(16)
4 LLN   = lower limit of normal

Biliary Tract Cancer
Locally advanced or metastatic BTC -TOPAZ-1
The safety of IMFINZI in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, a randomized, double-blind, placebo-controlled, multicenter trial. A total of 338 patients received IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks up to 8 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity. Patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or other active infections, including tuberculosis or hepatitis C were ineligible [see Clinical Studies (14.4)].


IMFINZI was discontinued due to adverse reactions in 6% of the patients receiving IMFINZI plus chemotherapy. The most frequently reported events resulting in discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). The remaining events were dispersed across system organ classes and reported in 1 patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), upper gastrointestinal hemorrhage (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and pyrexia.
Table 13 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy.


Table 13. Adverse Reactions Occurring in ≥ 10% of Patients in the TOPAZ-1 Study 

IMFINZI with Gemcitabine           Placebo with Gemcitabine and Cisplatin                     and Cisplatin
N = 338                           N = 342
Adverse Reaction       All   Grades*    Grade*   3-4 (%)   All Grades*    Grade* 3-4 (%) (%)                                    (%)
General disorders and administration site conditions
Fatigue†                           42                      6                43                   6 Pyrexia                            20                  1.5                  16                  0.6 Gastrointestinal disorders
Nausea                             40                  1.5                  34                  1.8 Constipation                       32                  0.6                  29                  0.3 Abdominal pain‡                    24                  0.6                  23                  2.9 Vomiting                           18                  1.5                  18                  2.0 Diarrhea                           17                  1.2                  15                  1.8 Metabolism and nutrition disorders
Decreased appetite                 26                  2.1                  23                  0.9 Skin and subcutaneous tissue disorders
Rash§                              23                  0.9                  14                   0 Pruritus                           11                      0                 8                   0 Psychiatric disorders
Insomnia                           10                      0                11                   0 * Graded according to NCI CTCAE version 5.0
† Includes fatigue, malaise, cancer fatigue and asthenia.
‡ Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
§ Includes rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash erythematous, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, erythema, dermatitis and rash.


Table 14 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy.

Table 14. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20%* of Patients in the TOPAZ-1 study


IMFINZI with Gemcitabine and         Placebo with
Cisplatin                         Gemcitabine and

Cisplatin
Laboratory Abnormality                          Grade† 3 or 4                      Grade† 3 or 4 (%)                                (%)
Chemistry
Hyponatremia                                          18                                 13 Gamma-glutamyltransferase                             12                                 13 increased
Increased bilirubin                                   10                                 14 Hypokalemia                                            8                                 4.4 Increased AST                                          8                                  8 Increased ALT                                        7                               6 Blood creatinine increased                           5                              2.1 Hypomagnesemia                                      4.5                             2.2 Hypoalbuminemia                                     3.6                             2.9 Hyperkalemia                                        2.1                             2.1 Increased Alkaline Phosphatase                      1.8                             3.8 Hypocalcemia                                       1.8                             2.4 Hematology
Neutropenia                                        48                               49 Anemia                                             31                               28 Leukopenia                                         28                               28 Lymphopenia                                         23                               15 Thrombocytopenia                                    18                               18 * The frequency cut off is based on any grade change from baseline
† Graded according to NCI CTCAE version 5.0. Each test incidence is based on the number of patients  who had both baseline and at least one on-study laboratory measurement available: IMFINZI + Gem/Cis 
(range: 312 to 335) and Placebo + Gem/Cis (range: 319 to 341).


Hepatocellular Carcinoma

Unresectable HCC - HIMALAYA
The safety of IMFINZI in combination with tremelimumab was evaluated in a total of 388  patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Clinical 
Studies (14.1)]. Patients received IMFINZI 1,500 mg administered as a single intravenous infusion in combination with tremelimumab 300 mg on the same day, followed by IMFINZI  every 4 weeks or sorafenib 400 mg given orally twice daily.

Serious adverse reactions occurred in 41% of patients who received IMFINZI in combination  with tremelimumab. Serious adverse reactions in > 1% of patients included hemorrhage 
(6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute  kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients  who received IMFINZI in combination with tremelimumab, including death (1%), hemorrhage  intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and 
immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in ≥ 
20% of patients) were rash, diarrhea, fatigue, pruritis, musculoskeletal pain, and abdominal
 pain.
Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (≥ 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%).

Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred  in 35% of patients. Adverse reactions which required dosage interruption or delay in ≥ 1% of  patients included ALT increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased 
(3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%),  pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis 
(1%), and blood creatinine increased (1%).

Table 15 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with tremelimumab in the HIMALAYA study.

Table 15. Adverse Reactions Occurring in ≥ 10% of Patients in the HIMALAYA study 
IMFINZI and                  Sorafeni
Tremelimumab                        b
(N=388)                   (N=374)

All             Grade 3-     All Grades       Grade 3-
Adverse Reaction                                                  (%) Grade          4 (%)                      4 (%) s (%)
Gastrointestinal disorders

Diarrhea*                              27              6         45              4.3 
Abdominal pain*                        20             1.8        24               4 
Nausea                                 12              0         14               0 
Skin and subcutaneous tissue disorders

Rash*                                  32             2.8        57               12 
Pruritus                                        23               0            6                0.3 
Metabolism and nutrition disorders

Decreased appetite                              17               1.3         18                0.8 
General disorders and administration site conditions

Fatigue*                                        26               3.9         30                 6 
Pyrexia*                                        13               0.3          9                0.3 
Psychiatric disorders

Insomnia                                        10               0.3         4.3                0 
Endocrine disorders
Hypothyroidism*                                 14               0            6                 0 
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain*                           22               2.6         17                0.8 
* Represents   a composite of multiple related terms.

Table 16 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with tremelimumab in the HIMALAYA study.

Table 16. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the HIMALAYA study

IMFINZI and                          Sorafeni
Tremelimumab                                b
Laboratory Abnormality             Any                Grade 3† or 4    Any                Grade 3† or 4 grade†             (%)‡           grade†               (%)‡
(%)‡                              (%)‡
Chemistry

Aspartate                               63                 27            55                    21 
Aminotransferase increased

Alanine Aminotransferase                56                 18            53                    12  increased

Sodium decreased                    46               15                 40                  11 
Bilirubin increased                 41                8                 47                  11 
Alkaline                                              8                 44                  5 41
Phosphatase increased
Glucose increased                   39               14                 29                  4 
Calcium decreased                   34                0                 43                 0.3 
Albumin decreased                   31               0.5                37                 1.7 
Potassium increased                 28               3.8                21                 2.6 
Creatinine increased                21               1.3                15                 0.9 
Hematology
Hemoglobin decreased                52               4.8                40                  6 
Lymphocytes decreased               41               11                 39                  10 
Platelets decreased                 29               1.6                35                 3.1 
Leukocytes decreased                20               0.8                30                 1.1 
†   Graded according to NCI CTCAE version 4.03.
‡   Each test incidence is based on the number of patients who had both baseline and at least one on-  study laboratory measurement available: IMFINZI with tremelimumab (range: 367-378) and sorafenib 
(range:344-352).


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il 

8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk summary
Based on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMFINZI in pregnant women.

In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus.


In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.


Data
Animal Data
As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth) and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.


8.2 Lactation
Risk Summary
There are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk.
The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMFINZI are unknown. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data).


Because of the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IMFINZI and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended duration to not breastfeed, as appropriate.


Data
In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death.


8.3 Females and Males of Reproductive Potential
Pregnancy testing
Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI.

Contraception
Females
IMFINZI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI, and for 3 months following the last dose of IMFINZI. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended contraception duration, as appropriate.

8.4 Pediatric Use
The safety and effectiveness of IMFINZI have not been established in pediatric patients.

8.5 Geriatric Use


No dose adjustment is required for elderly patients (≥ 65 years of age) (see section 14).

Of the 476 patients treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients.
Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older.
There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.
Of the 330 patients with metastatic NSCLC treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.
Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.
Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 
65 years of age and older and younger adult patients.
In studies PACIFIC, CASPIAN and TOPAZ-1 data on safety for patients 75 years and older are too limited to draw a conclusion on this population.
In first line metastatic NSCLC patients in the POSEIDON study, some differences in safety were reported between elderly (≥ 65 years) and younger patients. The safety data from patients 75 years of age or older are limited to a total of 74 patients. There was a higher frequency of serious adverse reactions and discontinuation rate of any study treatment due to adverse reactions in 35 patients aged 75 years of age or older treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy (45.7% and 28.6%, respectively) relative to 39 patients aged 75 years of age or older who received platinum-based chemotherapy only (35.9% and 20.5%, respectively).