Special Warning : אזהרת שימוש

5      WARNINGS AND PRECAUTIONS
5.1    Encephalopathy, Including Wernicke’s
Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC in clinical trials and 0.16% (1/608) of cases were fatal.
Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke’s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Dosage and Administration (2.6) and Adverse Reactions (6.1)].


5.2    Anemia and Thrombocytopenia

Treatment with INREBIC can cause anemia and thrombocytopenia.

Anemia
New or worsening Grade 3 anemia occurred in 34% of INREBIC-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of INREBIC-treated patients and permanent discontinuation of INREBIC occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent [see Dosage and Administration (2.5)].
Thrombocytopenia

New or worsening Grade ≥3 thrombocytopenia during the randomized treatment period occurred in 12% of INREBIC-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% of INREBIC-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of INREBIC-treated patients.
Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated. For Grade 3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated [see Dosage and Administration (2.5)].
5.3    Gastrointestinal Toxicity
Gastrointestinal toxicities are the most frequent adverse reactions in INREBIC-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patients, and vomiting in 39% of patients. Grade 3 diarrhea and vomiting occurred in 5% and 3.1% of patients, respectively. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment.
Consider providing appropriate prophylactic antiemetic therapy (e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms. For Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt INREBIC until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose [see Dosage and Administration (2.5)]. Monitor thiamine levels and replete as needed.
5.4    Hepatic Toxicity
Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of INREBIC-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months.
Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt INREBIC dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If reoccurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with INREBIC [see Dosage and Administration (2.5)].
5.5    Amylase and Lipase Elevation
Grade 3 or higher amylase and/or lipase elevations developed in 2% and 10%, respectively, of INREBIC- treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation.
Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher amylase and/or lipase elevations, interrupt INREBIC until resolved to Grade 1 or less or to baseline.
Restart dose at 100 mg daily below the last given dose [see Dosage and Administration (2.5)].
5.6      Major Adverse Cardiac Events (MACE)
Another Janus Kinase (JAK)-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which INREBIC is not indicated.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with INREBIC, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.
Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

5.7      Thrombosis

Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which INREBIC is not indicated. In patients with MF treated with INREBIC in clinical trials, the rates of thromboembolic events were similar in INREBIC and placebo treated patients.

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

5.8      Secondary Malignancies
Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding nonmelanoma skin cancer (NMSC) (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which INREBIC is not indicated. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with INREBIC, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.
5.9      Excipients
INREBIC capsules contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium free’.
5.10     Effects on ability to drive and use machines
INREBIC has minor influence on the ability to drive and use machines. Patients who experience dizziness after taking Inrebic should refrain from driving or using machines.

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/.

Effects on Driving