Special Warning : אזהרת שימוש

5   WARNINGS AND PRECAUTIONS

5.1 Myelosuppression
Difolta can cause myelosuppression, manifested by thrombocytopenia, neutropenia, and/or anemia.
Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related myelosuppression [see Dosage and Administration (2.1)]


Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose [ see Dosage and Administration (2.4)]

5.2 Mucositis
Difolta can cause mucositis [see Adverse Reactions (6.1)].

Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of mucositis [see Dosage and Administration (2.1)].

Monitor for mucositis weekly and omit and/or reduce the dose for grade 2 or higher mucositis [see Dosage and administration (2.4)].
5.3 Dermatologic Reactions
Difolta can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (2.1% of 663 patients) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN) [see Adverse Reactions (6.1, (6.2)]. They may be progressive and increase in severity with further treatment and may involve skin and subcutaneous sites of known lymphoma.

Monitor closely for dermatologic reactions. Withhold or discontinue Difolta based on severity [see Dosage and Administration (2.4)]

5.4 Tumor Lysis Syndrome
Difolta can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.

5.5 Hepatic Toxicity
Difolta can cause hepatic toxicity and liver function test abnormalities [see Adverse Reactions (6.1)]. Persistent liver function test abnormalities may be indicators of hepatic toxicity and require dose modification or discontinuation.

Monitor liver function tests. Omit dose until recovery, adjust or discontinue therapy based on the severity of the hepatic toxicity [see Dosage and Administration (2.2)].

5.6 Risk of Increased Toxicity with Renal Impairment
Patients with severe renal impairment(eGFR 15 to < 30mL/min/1.73 m2 based on MDRD) may be at greater risk for increased exposure and adverse reactions Reduce Difolta dosage in patients with severe renal impaiment see Dosage and Administration (2.2),]

Serious adverse drug reactions including toxic epidermal necrolysis (TEN) and mucositis were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered Difolta therapy.
Avoid Difolta use in patients with (ESRD) with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the Difolta dose based on adverse reactions [see Dosage and Administration (2.2)],


5.7 Embryo-Fetal Toxicity
Based on findings in animals and its mechanism of action, Difolta can cause fetal harm when administered to a pregnant woman. Difolta was embryotoxic and fetotoxic in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Difolta and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Difolta and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)]


6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: •   Myelosuppression (Bone Marrow Suppression) [see Warnings and Precautions (5.1)]
•   Mucositis [see Warnings and Precautions (5.2)]
•   Dermatologic Reactions [see Warnings and Precautions (5.3)]
•   Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
•   Hepatic Toxicity [see Warnings and Precautions (5.5)] The most common adverse reactions observed in patients with peripheral T-cell lymphoma (PTCL) treated with Difolta were mucositis, thrombocytopenia, nausea, and fatigue.

6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of Difolta was evaluated in study PDX-008 [see clinical studies (14)]. Patients received Difolta 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range: 1day to-1.5 years).
The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.
Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of Difolta. The most common serious adverse events (> 3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Across clinical trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients who received doses ranging from 30 mg/m2 to 325 mg/m2.
Twenty-three percent of patients (n = 25) discontinued treatment with Difolta due to adverse reactions. The most frequent adverse reactions reported as the reason for discontinuation of treatment were mucositis (6%) and thrombocytopenia (5%).
The most common adverse reactions (> 35%) were mucositis, thrombocytopenia, nausea, and fatigue.
Table 4 summarizes the adverse reactions in Study PDX-008.
Table 4   Adverse Reactions Occurring in PTCL Patients (Incidence ≥ 10% of patients) N=111
Total       Grade 3         Grade 4
Preferred Term                                              N     %      N     %         N    % Any Adverse Event                                          111   100    48     43        34   31 Mucositisa                                             78     70    19     17        4    4 b
Thrombocytopenia                                       45     41    15     14        21   19b Nausea                                                 44     40     4      4        0    0 Fatigue                                                40     36     5      5        2    2 Anemia                                                 38     34    17     15        2    2 Constipation                                           37     33     0      0        0    0 Pyrexia                                                36     32     1      1        1    1 Edema                                                  33     30     1      1        0    0 Cough                                                  31     28     1      1        0    0 Epistaxis                                              29     26     0      0        0    0 Vomiting                                               28     25     2      2        0    0 Neutropenia                                            27     24    14     13        8    7 Diarrhea                                               23     21     2      2        0    0 Dyspnea                                                21     19     8      7        0    0 Anorexia                                               17     15     3      3        0    0 Hypokalemia                                            17     15     4      4        1    1 Rash                                                   17     15     0      0        0    0 Pruritus                                               16     14     2      2        0    0 Pharyngolaryngeal pain                                 15     14     1      1        0    0 Liver function test abnormalc                          14     13     6      5        0    0 Abdominal pain                                         13     12     4      4        0    0 Pain in extremity                                      13     12     0      0        0    0 Back pain                                              12     11     3      3        0    0 Leukopenia                                             12     11     3      3        4    4 Night sweats                                           12     11     0      0        0    0 Asthenia                                               11     10     1      1        0    0 Tachycardia                                            11     10     0      0        0    0 Upper respiratory tract infection                      11     10     1      1        0    0 a
Stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts.
b
Five patients with platelets < 10,000/mcL c
Alanine aminotransferase, aspartate aminotransferase, and transaminases increased Serious Adverse Events
Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of Difolta. The most common serious adverse events (> 3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all Difolta trials at doses ranging from 30 to 325 mg/m2.

Discontinuations
Twenty-three percent of patients (n = 25) discontinued treatment with Difolta due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, n = 7) and thrombocytopenia (5%, n = 5).

Dose Modifications
The target dose of Difolta was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.

6.2 Post Marketing Experience

The following adverse reactions have been identified during postapproval use of Difolta.
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.
Dermatologic Reactions: Toxic epidermal necrolysis.

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/

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