Adverse reactions : תופעות לוואי

7       ADVERSE REACTIONS
The following adverse reactions are also discussed in greater details in other sections of the labeling:
•       Hyperglycemia [see Warnings and Precautions (6.1)]
•       Diarrhea [see Warnings and Precautions (6.2)]
•       Cutaneous Adverse Reactions [see Warnings and Precautions (6.3)] 

7.1        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 population described in WARNINGS and PRECAUTIONS reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with fulvestrant, in 355 patients in CAPItello-291 until disease progression or unacceptable toxicity. Among the 355 patients who received TRUQAP, 52% were exposed for 6 months or longer, and 27% were exposed for greater than one year. In this safety population, the most common (≥20%) adverse reactions including laboratory abnormalities were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%),
decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).

CAPItello-291
The safety of TRUQAP was evaluated in CAPItello-291, a clinical trial including 288 adult patients (155 patients in TRUQAP with fulvestrant arm and 133 patients in placebo with fulvestrant arm) whose breast cancer had one or more PIK3CA/AKT1/PTEN-alterations [see Clinical Studies (13)]. Among patients who received TRUQAP, 61% were exposed for 6 months or longer and 30% were exposed for greater than one year.

Of the 155 patients who received TRUQAP with fulvestrant, the median age was 58 years (range 36 to 84); female (99%); White (48%), Asian (31%), Black (1.3%), American Indian/Alaska Native (0.6%), and other races (19%).
Serious adverse reactions occurred in 18% of patients receiving TRUQAP with fulvestrant. The most common serious adverse reactions (≥1%) were cutaneous adverse reaction (3.9%), diarrhea and pneumonia (2.6% each), vomiting and pyrexia (1.9% each), hyperglycemia, hypersensitivity, fatigue, renal injury and second malignancy (1.3% each).
Fatal adverse reactions occurred in 1.3% of patients who received TRUQAP with fulvestrant, including sepsis (0.6%), and acute myocardial infarction (0.6%).


Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. The most common adverse reaction (≥ 2%) leading to permanent discontinuation of TRUQAP was cutaneous adverse reactions (6%). Dosage interruptions of TRUQAP due to an adverse reaction occurred in 39% of patients.
Adverse reactions leading to dosage interruption in ≥ 2% of patients included cutaneous adverse reactions (14%), diarrhea (10%), pyrexia (4.5%), vomiting and nausea (3.2% each), and fatigue (2.6%).

Dose reductions of TRUQAP due to adverse reactions occurred in 21% of patients receiving TRUQAP with fulvestrant. Adverse reactions leading to TRUQAP dose reductions in ≥ 2% of patients were diarrhea and cutaneous adverse reactions (8% each).

The most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (77%), increased random glucose (58%), cutaneous adverse reaction (56%), decreased lymphocytes (49%) decreased hemoglobin (47%), fatigue (38%), increased fasting glucose (37%), nausea and decreased leukocytes (35% each), increased triglycerides (30%), stomatitis (25%), decreased neutrophils (25%), and vomiting (21%). Adverse reactions and laboratory abnormalities are listed in Table 4 and Table 5, respectively.


Table 4. Adverse Reactions ≥ 10% in patients who Received TRUQAP with Fulvestrant [with a Difference Between Arms of ≥ 3%] in CAPItello-291


Adverse Reaction       TRUQAP with                          Placebo with Fulvestrant                        Fulvestrant
N=155                              N=133
All Grades     Grade 3 or 4         All Grades     Grade 3 or 4
%              %                    %             %
Gastrointestinal Disorders
Diarrhea                 77           12                     19                 0.8 Nausea                   35           1.3                    14                 0.8 Stomatitis*              25           1.9                     5                  0 Vomiting                 21           1.9                     7                 0.8 Skin and Subcutaneous Tissue Disorders
Cutaneous adverse        56            15                    16                 0.8 reactions†
General Disorders and Administration Site Conditions
Fatigue*                38              1.9                  27                 1.5 Metabolism and Nutrition Disorders
Hyperglycemia‡          19              1.9                  4.5                0 
Decreased appetite     17                   0                 8                 0.8 Nervous System Disorders
Headache*              17                   0                13                 0.8 Infections and Infestations
Urinary tract             14               0.6                5                 0 infection*
Renal and Urinary disorders
Renal injury§           11                             2.6                  1.5                   0.8 * Includes other related terms.
†Cutaneous adverse reaction includes butterfly rash, dermatitis, allergic dermatitis, dry skin, eczema, erythema multiforme, hand dermatitis, palmar-plantar erythrodysesthesia syndrome, pruritus, rash, erythematous rash, maculo- papular rash, papular rash, skin discoloration, skin fissures, skin reaction, skin ulcer, urticaria, purpura, erythema and drug eruption.
‡ Hyperglycemia includes hyperglycemia, blood glucose increased, glycosylated hemoglobin increased, glucose tolerance impaired and diabetes mellitus.
§ Renal injury includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, increased creatinine and proteinuria.


Clinically relevant adverse reactions occurring in < 10% of patients treated with TRUQAP included anemia, hypersensitivity (including anaphylactic reaction), dysgeusia, dyspepsia, pneumonia and pyrexia.


Table 5: Laboratory Abnormalities (> 10%) in patients who Received TRUQAP with Fulvestrant [With a Difference Between Arms >3%] in CAPltello-291
Laboratory               TRUQAP with Fulvestrant*       Placebo with Fulvestrant† All Grades   Grade 3 or 4     All Grades   Grade 3 or 4
Abnormality                 (%)           (%)             (%)           (%) Glucose Metabolism
Increased                    58             9              17            0 random glucose
Increased                    37           0.6              29            0 fasting glucose
Hematology
Decreased                    49            11              14           2.3 lymphocytes
Decreased                    47             2              22           2.3 hemoglobin
Decreased leukocytes         35           0.6              23            0 Decreased neutrophils        25           1.9              16           0.8 Decreased platelets          12           1.9               6           0.8 Other Categories
Increased triglycerides      30           0.7              22           0.9 Increased                    23           2.6              13            0 alanine aminotransfera se
Electrolytes/Renal
Decreased                          19                 0.6                 8                   0 corrected calcium
Increased creatinine               19                 1.3                4.6                0.8 Decreased potassium                17                 4.5                 8                  0 *The denominator used to calculate the rate varied from 129 to 155 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 109 to 131 based on the number of patients with a baseline value and at least one post-treatment value.


Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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