Adverse reactions : תופעות לוואי

6        ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling: 
•     Encephalopathy, including Wernicke’s [see Warnings and Precautions (5.1)] •     Anemia and Thrombocytopenia [see Warnings and Precautions (5.2)] •    Gastrointestinal Toxicity [see Warnings and Precautions (5.3)] •    Hepatic Toxicity [see Warnings and Precautions (5.4)]
•    Amylase and Lipase Elevation [see Warnings and Precautions (5.5)] •    Major Adverse Cardiac Events [see Warnings and Precautions (5.6)] •    Thrombosis [see Warnings and Precautions (5.7)]
•    Secondary Malignancies [see Warnings and Precautions (5.8)]

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 5.1 Encephalopathy, including Wernicke’s, reflect exposure to INREBIC as a single agent in 608 patients who received more than one dose (ranging from 30 mg to 800 mg) in Studies JAKARTA, ARD11936, JAKARTA2, ARD12042, ARD12888, TED12037/TED12015, INT12497, and TES13519, of whom 459 were patients with myelofibrosis, including 97 patients previously treated with ruxolitinib. Among the 608 patients receiving INREBIC, the median drug exposure was 37 weeks and the median number of cycles initiated was 9 cycles. Fifty-nine percent of 608 patients were exposed for 6 months or longer and 39% were exposed for 12 months or longer.
Using the dataset described above, the most common adverse reactions in >20% of patients (N=608) were diarrhea, nausea, anemia, vomiting, fatigue, thrombocytopenia, and constipation.

JAKARTA Trial
The safety of INREBIC was evaluated in the randomized treatment period of the JAKARTA trial [see Clinical Studies (14)]. Key eligibility criteria included adult patients with intermediate-2 or high-risk primary MF or post-PV MF or post-ET MF with splenomegaly, platelet count ≥50 x 10 9/L, and no splenectomy. Patients received INREBIC at 400 mg daily (n=96) or placebo (n=95). Among patients receiving INREBIC, 82% were exposed for more than 6 months and 65% for more than one year. Patients had a median duration of exposure to INREBIC 400 mg daily of 15.5 months compared with placebo where patients were treated for 6 months or until disease progression after which patients were allowed to crossover to active treatment. The median age of patients who received INREBIC was 65 years (range: 27 to 86 years), 59% were male, 90% were White, 8% were Asian, 1% were Black, 1% were Other, and 92% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

Serious adverse reactions occurred in 21% of INREBIC-treated patients. Serious adverse reactions in ≥2% of patients receiving INREBIC 400 mg daily included cardiac failure (5%) and anemia (2%). Fatal adverse reactions of cardiogenic shock occurred in 1% of patients receiving INREBIC 400 mg daily.
Permanent discontinuation due to an adverse reaction occurred in 14% of patients receiving INREBIC. Most frequent reasons for permanent discontinuation in ≥2% of patients receiving INREBIC included cardiac failure (3%), thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine (2% each).
Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received INREBIC. Adverse reactions requiring dosage interruption in >3% of patients who received INREBIC included diarrhea and nausea.
Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received INREBIC. Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).
The most common adverse reactions (reported in ≥20%) were diarrhea, nausea, anemia, and vomiting.
Tables 3 and 4 summarize the common adverse reactions and laboratory abnormalities, respectively, in JAKARTA during randomized treatment.

Table 3: Adverse Reactions Reported in ≥5% Patients Receiving INREBIC 400 mg with a Difference between Arms of >5% during Randomized Treatment

INREBIC 400 mg                   Placebo
(n=96)                       (n=95)
All Grades   Grade ≥3b    All Grades          Grade ≥3
Adverse Reaction    a
%           %              %                %
Diarrhea                           66            5            16                 0 Nausea                             62            0            15                 0 Anemia                             40            30           14                 7 Vomiting                           39            3.1           5                 0 Fatigue or asthenia                19            5            16                1.1 Muscle spasms                      12            0            1.1                0 Blood creatinine increased         10            1            1.1                0 Pain in extremity                  10            0            4.2                0 Alanine aminotransferase                         0
9                         1.1                0
Increased
Headache                            9            0            1.1                0 Weight increased                    9            0            4.2                0 Dizziness                           8            0            3.2                0 Bone pain                           8            0            2.1                0 Urinary tract infectionc            6            0            1.1                0 Dysuria                             6            0             0                 0 Aspartate aminotransferase                       0
5                         1.1                0 increased a
CTCAE version 4.03.
b
Only 1 Grade 4 event (anemia).
c
Includes cystitis.


Clinically significant adverse reactions reported in 5% or less of patients: hypertension of all grades was reported in 4.2% of patients and Grade 3 or higher in 3% of INREBIC-treated patients.

Changes in selected postbaseline laboratory values that were observed are shown in Table 4 for the JAKARTA trial during randomized treatment.



Table 4: Selected Laboratory Abnormalities That Have Worsened from Baseline (≥20%) in Patients Receiving INREBIC with a Difference between Arms of >10% When Compared to Placebo in JAKARTA during Randomized Treatment

INREBIC 400 mg                       Placebo
(n=96)                           (n=95)
Laboratory Parameter              All Grades          Grade ≥3   All Grades          Grade ≥3 %                  %            %                %
Hematology
Anemia                              74                34            32               10 Thrombocytopenia                    47                12            26               10 Neutropenia                         23                 5            13               3.3 Biochemistry
Creatinine increased                59                3.1           19               1.1 ALT increased                       43                 1            14                0 AST increased                       40                 0            16               1.1 Lipase increased                    35                10            7                2.2 Hyponatremia                        26                 5            11               4.3 Amylase increased                   24                2.1           5                 0 

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/.