Adverse reactions : תופעות לוואי

8   ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
•    Severe Hypersensitivity [see Warnings and Precautions (7.1)]
•    Severe Cutaneous Adverse Reactions [see Warnings and Precautions (7.2)]
•    Hyperglycemia [see Warnings and Precautions (7.3)]
•    Pneumonitis [see Warnings and Precautions (7.4)]
•    Diarrhea or Colitis [see Warnings and Precautions (7.5)] 8.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of PIQRAY was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in 571 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer enrolled into two cohorts, with or without a PIK3CA mutation [see Clinical Studies (15)].
Patients received either PIQRAY 300 mg plus fulvestrant (n = 284) or placebo plus fulvestrant (n = 287). Fulvestrant 500 mg was administered intramuscularly on Cycle 1, Day 1 and 15, and then at Day 1 of each 28-day cycle during treatment PIQ API FEB24 V6                                                                            USPI JAN24 phase.
Two patients (0.7%) died while on treatment with PIQRAY plus fulvestrant due to causes other than the underlying malignancy. Causes of death included one cardio-respiratory arrest and one second primary malignancy. Neither was suspected to be related to study treatment.
Serious adverse reactions occurred in 35% of patients receiving PIQRAY plus fulvestrant. Serious adverse reactions in > 2% of patients receiving PIQRAY plus fulvestrant included hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%).
Osteonecrosis of the jaw (ONJ) was reported in 4.2% of patients (12/284) in the PIQRAY plus fulvestrant arm compared to 1.4% of patients (4/287) in the placebo arm.
All patients experiencing ONJ had prior or concomitant bisphosphonates or RANK- ligand inhibitor administration.
Among patients receiving PIQRAY plus fulvestrant, 4.6% permanently discontinued both PIQRAY and fulvestrant and 21% permanently discontinued PIQRAY alone, due to ARs.
The most frequent ARs leading to treatment discontinuation of PIQRAY in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).
Dose reductions due to ARs occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent ARs leading to dose reduction in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (29%), rash (9%), diarrhea (6%), stomatitis (3.5%), and mucosal inflammation (2.1%).
The most common adverse reactions, including laboratory abnormalities (all grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, gamma-glutamyl transferase (GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, activated partial thromboplastin time (aPTT) prolonged, and alopecia.
Adverse reactions and laboratory abnormalities are listed in Table 6 and Table 7, respectively.


Table 6: Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher than Placebo Arm in SOLAR-1 (All Grades)

PIQRAY plus fulvestrant               Placebo plus fulvestrant
N = 284                               N = 287

Adverse reactions                        All Grades           Grade 3-4         All Grades           Grade 3-4 %                   %                  %                   %
Gastrointestinal disorders
Diarrhea                                       58                7*                 16                  0.3* Nausea                                         45               2.5*                22                  0.3* 
PIQ API FEB24 V6                                                                         USPI JAN24 Stomatitis1                                                        30                        2.5*                6           0* Vomiting                                                           27                        0.7*               10          0.3* Abdominal pain2                                                    17                        1.4*               11           1* Dyspepsia                                                          11                         0*                 6           0* General disorders and administration site conditions
Fatigue3                                                           42                         5*                29           1* Mucosal inflammation                                               19                        2.1*                1           0* Edema peripheral                                                   15                         0*                 5          0.3* Pyrexia                                                            14                        0.7                4.9         0.3* Mucosal dryness4                                                   12                        0.4*               4.2          0* Infections and infestations
Urinary tract infection5                                           10                        0.7*                5           1* Investigations
Weight decreased                                                   27                        3.9*               2.1          0* Metabolism and nutrition disorders
Decreased appetite                                                 36                        0.7*               10          0.3* Nervous system disorders
Dysgeusia6                                                         18                        0.4*               3.5          0* Headache                                                           18                        0.7*               13           0* Skin and subcutaneous tissue disorders
Rash7                                                              52                        20*                 7          0.3* Alopecia                                                           20                         0*                2.4          0* Pruritus                                                           18                        0.7*                6           0* Dry skin8                                                          18                        0.4*               3.8          0* 
Grading according to CTCAE Version 4.03.
1
Stomatitis: including stomatitis, aphthous ulcer and mouth ulceration.
2
Abdominal pain: abdominal pain, abdominal pain upper, abdominal pain lower.
3
Fatigue: including fatigue, asthenia.
4
Mucosal dryness: including dry mouth, mucosal dryness, vulvovaginal dryness.
5
Urinary tract infection: including UTI and single case of urosepsis.
6
Dysgeusia: including dysgeusia, ageusia, hypogeusia.
7
Rash: including rash, rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic.
8
Dry skin: including dry skin, skin fissures, xerosis, xeroderma.
*
No Grade 4 adverse reactions were reported.


Among the patients with Grade 2 or 3 rash, the median time to first onset of Grade 2 or 3 rash was 12 days. A subgroup of 86 patients received premedication, including antihistamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all grades rash (27% vs 54%), Grade 3 rash (12% vs 20%) and rash leading to permanent discontinuation of PIQRAY (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash.


PIQ API FEB24 V6                                                                                              USPI JAN24 Table 7: Laboratory Abnormalities Occurring in ≥ 10% of Patients in SOLAR-1 PIQRAY plus fulvestrant             Placebo plus fulvestrant
N = 284                            N = 287

All Grades                Grade 3-4   All Grades             Grade 3-4 Laboratory abnormality                                            %                        %             %                    % Hematological parameters
Lymphocyte count decreased                                         52                      8           40                    4.5* Hemoglobin decreased                                               42                     4.2*         29                     1* Activated partial thromboplastin time                              21                     0.7*         16                    0.3* (aPTT) prolonged
Platelet count decreased                                           14                      1.1          6                     0* Biochemical parameters
Glucose increased1                                                 79                      39          34                     1 Creatinine increased                                               67                     2.8*         25                    0.7* 
Gamma glutamyl transferase (GGT)                                   52                      11          44                     10 increased
Alanine aminotransferase (ALT) increased                           44                      3.5         34                    2.4* Lipase increased                                                   42                      7           25                     6 Calcium (corrected) decreased                                      27                      2.1         20                     1.4 Glucose decreased                                                  26                      0.4         14                     0* Potassium decreased                                                14                      6           2.8                   0.7* Albumin decreased                                                  14                      0*           8                     0* Magnesium decreased                                                11                     0.4*         4.2                    0* 1
Glucose increase is an expected laboratory abnormality of PI3K inhibition.
*
No Grade 4 laboratory abnormalities were reported.



8.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of PIQRAY. 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.
Eye disorders: Uveitis
Gastrointestinal disorders: Colitis
Metabolism and nutrition disorders: Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS).
Skin and subcutaneous tissue disorders: Angioedema, Drug reaction with eosinophilia and systemic symptoms (DRESS).

PIQ API FEB24 V6                                                                                            USPI JAN24 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/