Indications : התוויות

Therapeutic Indications                                                                                                                                                                                                                                                                                                  mutagenic. Because of the possibility of infertility as a consequence the patient experiences myelosuppression-associated complications,               the discretion of the treating physician.                                     Use in patients with hepatic impairment has not been established.               of Decitabine-Trima 50 mg/vial therapy, men should seek advice on          Gastro-esophageal reflux                                Nervous system disorders                                                General disorders and administration site conditions    Hypertension                                  6 (6) Decitabine-Trima 50 mg/vial is indicated for the treatment of patients                                                                                                                                                                                                                                                                                                                                                                 4 (5)          0 (0) with myelodysplastic syndromes (MDS) including previously treated and          such as those described below:                                                   Special Populations:                                                          Caution should be exercised in the administration of Decitabine-Trima           conservation of sperm and female patients of childbearing potential        Disease                                                 Headache                          23 (28)             11 (14) untreated, de novo and secondary MDS of all French-American-British            • Febrile neutropenia (temperature ≥ 38.5°C and absolute neutrophil              Paediatric population                                                         50 mg/vial to patients with hepatic impairment and in patients who              should seek consultation regarding oocyte cryopreservation prior to        Glossodynia                   4 (5)          0 (0) Asthenia                              15 (15)           Hypotension                                   11 (11) subtypes (refractory anemia, refractory anemia with ringed sideroblasts,           count < 1,000/μL)                                                            The safety and efficacy of Decitabine-Trima 50 mg/vial in children            develop signs or symptoms of hepatic impairment. Liver function tests           initiation of treatment with Decitabine-Trima 50 mg/vial.                                                                          Dizziness                         15 (18)             10 (12)           Chest pain                            6 (6)             * In this single arm study, investigators reported adverse events refractory anemia with excess blasts, refractory anemia with excess            • Active viral, bacterial or fungal infection (i.e., requiring intravenous       aged < 18 years have not yet been established. No data are available.         should be performed prior to initiation of therapy and prior to each            4.7. Effects on Ability to Drive and Use Machines                          General disorders and administrative site disorders     Hypoesthesia                      9 (11)              1 (1)                                                                        based on clinical signs and symptoms rather than predefined Chills                                16 (16) anti-infectives or extensive supportive care)                                                                                                              treatment cycle, and as clinically indicated (see sections 4.2 and 5.2).        Decitabine-Trima 50 mg/vial has moderate influence on the ability to                                                                                                                                                                                                  laboratory abnormalities. Thus not all laboratory abnormalities blasts in transformation, and chronic myelomonocytic leukemia) and
Intermediate-1, Intermediate-2, and High-Risk International Prognostic         • Haemorrhage (gastrointestinal, genito-urinary, pulmonary with Hepatic impairment
Studies in patients with hepatic impairment have not been conducted.          Renal impairment                                                                drive and use machines. Patients should be advised that they may Pyrexia                       44 (53)        23 (28)    Psychiatric disorders                                                   Fatigue                               46 (46)              were recorded as adverse events.                                         Decitabine -Trima platelets < 25,000/μL or any central nervous system haemorrhage)                                                                                                                                                                           experience undesirable effects such as anemia during treatment.            Edema peripheral              21 (25)        13 (16) Scoring System groups.
Decitabine-Trima 50 mg/vial is indicated for the treatment of adult patients   Treatment with Decitabine-Trima 50 mg/vial may be resumed once The need for dose adjustment in patients with hepatic impairment has not been evaluated. Decitabine-Trima 50 mg/vial should be used with
Use in patients with severe renal impairment has not been studied.
Caution should be exercised in the administration of Decitabine-Trima 50        Therefore, caution should be recommended when driving a car or             Rigors                        18 (22)        14 (17) Insomnia                          23 (28)             11 (14)           Mucosal inflammation                  9 (9)            No overall difference in safety was detected between patients >65 years of age and younger patients in these MDS trials. No significant 50 mg/vial
Confusional state                 10 (12)             3 (4) with newly diagnosed de novo or secondary acute myeloid leukaemia              these conditions have improved or have been stabilized with adequate             caution in these patients. If worsening hepatic function occurs, patients     mg/vial to patients with severe renal impairment (Creatinine Clearance          operating machines.                                                                                                                                                                                        Edema                                 5 (5)            differences in safety were detected between males and females.
(AML), according to the World Health Organisation (WHO) classification,        treatment (anti-infective therapy, transfusions, or growth factors).             should be carefully monitored (see sections 4.4 and 5.2).                     [CrCl] <30 ml/min) and these patients should be monitored closely               4.8. Undesirable Effects Edema NOS                     15 (18)        5 (6)      Anxiety                           9 (11)              8 (10)            Edema peripheral                      27 (27)          Patients with renal or hepatic dysfunction were not studied. Insufficient         P00001568 0823B who are not candidates for standard induction chemotherapy.                    In clinical studies, approximately one-third of patients receiving                                                                                             (see section 4.2). Renal function tests should be performed prior to            MDS                                                                        Pain NOS                      11 (13)        5 (6)                                                                                                                                     numbers of non White patients were available to draw conclusions in Decitabine-Trima 50 mg/vial required a dose-delay. Dose reduction                Renal impairment                                                                                                                                                                                                                                                                                 Renal and urinary disorders                                             Pain                                  5 (5) 4.2. Posology and Method of Administration                                                                                                                      Studies in patients with renal impairment have not been conducted.            initiation of therapy and prior to each treatment cycle, and as clinically      Clinical Studies Experience                                                                                                                                                                                                                                       these clinical trials.
is not recommended.                                                                                                                                            indicated (see section 4.2).                                                                                                                               Lethargy                      10 (12)        3 (4)      Dysuria                           5 (6)               3 (4) Decitabine-Trima 50 mg/vial administration must be initiated under the                                                                                          Decitabine-Trima 50 mg/vial should be used with caution in these                                                                                              Because clinical trials are conducted under widely varying conditions,                                                                                                                                     Pyrexia                               36 (36)          Serious Adverse Events that occurred in patients receiving decitabine supervision of physicians experienced in the use of chemotherapeutic           In MDS                                                                           patients.                                                                     Cardiac disease                                                                 adverse reaction rates observed in the clinical trials of a drug cannot    Tenderness NOS                9 (11)         0 (0)      Urinary frequency                 4 (5)               1 (1)                                                                    50 mg/vial not previously reported in Tables 1 and 2 include: agents.                                                                        3-Day Dosing Regimen                                                                                                                                           Patients with a history of severe congestive heart failure or clinically        be directly compared to rates in the clinical trials of another drug and                                                                                                                                   Infections and infestations                            • Allergic Reaction: hypersensitivity (anaphylactic reaction).
The need for dose adjustment in patients with renal impairment has                                                                                                                                                                       Fall                          7 (8)          3 (4) Posology                                                                       Dose Regimen Modifications in the First 3 Cycles                                 not been evaluated (see sections 4.4 and 5.2).                                unstable cardiac disease were excluded from clinical studies and                may not reflect the rates observed in practice.                                                                                    Respiratory, thoracic and Mediastinal disorders                         Cellulitis                            9 (9)            • Blood and Lymphatic System Disorders: myelosuppression, There are 2 regimens recommended for Decitabine-Trima 50 mg/vial               During the first cycles of treatment, Grade 3-4 cytopenias are common            The use of Decitabine-Trima 50 mg/vial in patients with renal or hepatic      therefore the safety and efficacy of Decitabine-Trima 50 mg/vial in             Most Common Adverse Reactions: neutropenia, thrombocytopenia,              Chest discomfort              6 (7)          3 (4)      Cough                             33 (40)             25 (31)                                                                      splenomegaly.
administration. A 5-Day dosing regimen in the treatment of AML, and                                                                                                                                                                           these patients has not been established. Cases of cardiomyopathy                anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation,                                                                                                                                          Oral candidiasis                      6 (6) and may not represent progression of MDS. Pre-treatment cytopenias               impairment has not been established. Caution should be exercised                                                                                                                                                                         Intermittent pyrexia          5 (6)          3 (4)                                                                                                                                     • Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, a 3-Day or 5-Day dosing regimen in the treatment of MDS.                       may not improve until after Cycle 3.                                             in the administration of Decitabine-Trima 50 mg/vial to patients with         with cardiac decompensation, in some cases reversible after treatment           diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical             Malaise                       4 (5)          1 (1) Pharyngitis                       13 (16)             6 (7)             Pneumonia                             20 (20)              cardiomyopathy, atrial fibrillation, supraventricular tachycardia.       Decitabine -Trima Pre-medication for the prevention of nausea and vomiting is not routinely      For the first 3 cycles, to optimize patient benefit in the setting of moderate   hepatic or renal impairment and patients should be monitored closely          discontinuation, dose reduction or corrective treatment, have been                                                                                                                                                 Crackles lung                     12 (14)             1 (1)                                                                    • Gastrointestinal Disorders: gingival pain, upper gastrointestinal recommended but may be administered if required.                               neutropenia (absolute neutrophil count < 1000/µL), all attempts should           for signs of toxicity.                                                        reported in the postmarketing setting. Patients, especially those with          Intervention and or Dose Modification in the                               Crepitations NOS              4 (5)          1 (1) Sinusitis                             6 (6) hemorrhage.                                                                 50 mg/vial MDS                                                                            be made to maintain full dose treatment at the standard treatment cycle          Geriatric Use cardiac disease history, should be monitored for signs and symptoms             Controlled Supportive Care Study in the decitabine 50 mg/vial Arm:                                                                 Breath sounds decreased           8 (10)              7 (9)             Staphylococcal bacteremia             8 (8)            • General Disorders and Administrative Site Conditions: chest pain, There are two regimens for Decitabine-Trima 50 mg/vial administration                                                                                                                                                                         of heart failure.                                                               • Discontinuation: thrombocytopenia, neutropenia, pneumonia,               Catheter site erythema        4 (5)          1 (1)      Hypoxia                           8 (10)              4 (5)                                                                        catheter site hemorrhage.
interval. Concomitant antimicrobial prophylaxis as per institutional             Of the total number of MDS patients exposed to Decitabine-Trima 50                                                                                                                                                                                                                                                                                                       Tooth abscess                         5 (5) for MDS. With either regimen It is recommended that patients be treated        guidelines can be administered until recovery of granulocytes to above           mg/vial in the controlled clinical trial, 61 of 83 patients were age 65       Differentiation syndrome                                                            Mycobacterium avium complex infection, cardio-respiratory arrest,      Catheter site pain            4 (5)          0 (0)                                                                                                                                     • Hepatobiliary Disorders: cholecystitis.                                         P00001568 0823B Rales                             7 (8)               2 (2) for a minimum of 4 cycles; however, a complete or partial response             500/µL. Clinicians should also consider the need for early administration        and over, while 21 of 83 patients were age 75 and over. No overall            Cases of differentiation syndrome (also known as retinoic acid syndrome)            increased blood bilirubin, intracranial hemorrhage, abnormal liver                                                                                                                                     Upper respiratory tract infection     10 (10)          • Infections and Infestations: fungal infection, sepsis, bronchopulmonary have been reported in patients receiving decitabine. Differentiation                                                                                       Injection site swelling       4 (5)          0 (0) may take longer than 4 cycles.                                                 of growth factors during this time for the prevention or treatment of            differences in safety or effectiveness were observed between these                                                                                                function tests.                                                                                                                Postnasal drip                    4 (5)               2 (2)             Urinary tract infection               7 (7)                aspergillosis, peridiverticular abscess, respiratory tract infection, Complete blood counts and platelet counts should be performed as               infections in patients with MDS.                                                 subjects and younger subjects, and other reported clinical experience         syndrome may be fatal (see section 4.8). Treatment with high-dose IV            • Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation,         Hepatobiliary Disorders                                                                                                                                                                    pseudomonal lung infection, Mycobacterium avium complex infection.
Skin and subcutaneous tissue disorders needed to monitor response and toxicity, but at a minimum, prior to            Similarly, to optimize patient benefit in the setting of moderate                has not identified differences in responses between the elderly and           corticosteroids and haemodynamic monitoring should be considered at                 central line infection, febrile neutropenia.                                                                                                                                                           Injury, poisoning and procedural complications         • Injury, Poisoning and Procedural Complications: post procedural each cycle. Liver chemistries and serum creatinine should be obtained          thrombocytopenia (platelet count <25,000/µL), all attempts should                younger patients, but greater sensitivity of some older individuals           first onset of symptoms or signs suggestive of differentiation syndrome.        • Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy,           Hyperbilirubinemia            12 (14)        4 (5)      Ecchymosis                        18 (22)             12 (15)           Contusion                             9 (9)                pain, post procedural hemorrhage.
prior to initiation of treatment.                                              be made to maintain full dose treatment at the standard treatment                cannot be ruled out.                                                          Temporary discontinuation of Decitabine-Trima 50 mg/vial should be                  edema, tachycardia, depression, pharyngitis.                           Infections and Infestations                                                                                                                                                            • Nervous System Disorders: intracranial hemorrhage.
Rash NOS                          16 (19)             7 (9)
In the AML Phase 3 study, the median time to response (complete                cycle interval with concomitant administration of platelet transfusions          Method of Administration considered until resolution of symptoms and if resumed, caution is              Discussion of Adverse Reactions Information                                Pneumonia NOS                 18 (22)        11 (14) Investigations                                         • Psychiatric Disorders: mental status changes.
remission [CR] or CR with incomplete platelet recovery [CRp]) was              in case of bleeding events.                                                                                                                                    advised.                                                                                                                                                                                                           Erythema                          12 (14)             5 (6) 4.3 months. In MDS, the median time to response (CR+PR) in the                 Dose Modifications After Cycle 3
Decitabine-Trima 50 mg/vial is administered by intravenous infusion. A central venous catheter is not required. For instructions on reconstitution   Excipients The safety of decitabine 50 mg/vial was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study    Cellulitis                    10 (12)        6 (7)      Skin lesion NOS                   9 (11)              3 (4) Blood bilirubin increased             6 (6)            • Renal and Urinary Disorders: renal failure, urethral hemorrhage.
• Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung          Decitabine -Trima Phase 2 MDS studies with the 5-Day dosing regimen was 3.5 cycles.              If hematologic recovery (absolute neutrophil count ≥ 1,000/μL and                and dilution of the medicinal product before administration, see section      This medicine contains 0.5 mmol potassium per vial. After reconstitution        (N = 83 decitabine 50 mg/vial, N = 81 supportive care). The data           Candidal infection NOS        8 (10)         1 (1) Breath sounds abnormal                5 (5)                infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.       50 mg/vial In the Phase 3 MDS study with the 3-Day dosing regimen, the median             platelets ≥ 50,000/μL) from a previous Decitabine-Trima 50 mg/vial               9.2.                                                                          and dilution of the solution for intravenous infusion, this medicine            described below reflect exposure to decitabine 50 mg/vial in 83 patients                                                           Pruritis                          9 (11)              2 (2)             Weight decreased                      9 (9)            Post marketing Experience time to response was 3 cycles. Treatment may be continued as long                                                                                                                                                                                                                                                                                                                                        Catheter related infection    7 (8)          0 (0) as the patient shows response, continues to benefit or exhibits stable treatment cycle with persistent cytopenia(s) being considered related            4.3. Contraindications                                                        contains less than 1 mmol (39 mg) of potassium per dose, i.e. essentially       in the MDS trial. In the trial, patients received 15 mg/m2 intravenously                                                           Alopecia                          7 (8)               1 (1)             Metabolism and nutrition disorders                     The following adverse reactions have been identified during post to drug administration, requires more than 6 weeks, then the next cycle                                                                                        ‘potassium-free’.                                                               every 8 hours for 3 days every 6 weeks. The median number of decitabine    Urinary tract infection                                                                                                                                                                approval use of decitabine 50 mg/vial. Because these reactions are disease, i.e., in the absence of overt progression.                                                                                                             - Hypersensitivity to decitabine or to any of the excipients, listed in                                                                                                                                                                                                6 (7)          1 (1)      Urticaria NOS                     5 (6)               1 (1)                                                                                                                                                      P00001568 0823B of Decitabine-Trima 50 mg/vial therapy should be delayed and dosing                  section 6.1.                                                              This medicine contains 0.29 mmol sodium per vial. After reconstitution          50 mg/vial cycles was 3 (range 0 to 9).                                    NOS                                                                                                                             Anorexia                              23 (23)          reported voluntarily from a population of uncertain size, it is not always If after 4 cycles, the patient’s hematological values (e.g., platelet counts   reduced by the algorithm below. All dose reductions that occur should                                                                                          and dilution of the solution for intravenous infusion, this medicine            Table 1 presents all adverse events regardless of causality occurring - Breast feeding (see warnings and precautions)                                                                                                                                                                                                                                                  Swelling face                     5 (6)               0 (0)                                                                    possible to reliably estimate their frequency or establish a causal or absolute neutrophil count [ANC]), have not returned to pre-treatment        remain in effect for the duration of the chemotherapy; there should be                                                                                         contains between 13.8 mg-138 mg (0.6-6 mmol) sodium per dose                    in at least 5% of patients in the decitabine 50 mg/vial group and at a     Staphylococcal infection      6 (7)          0 (0)                                                                              Decreased appetite                    8 (8) relationship to drug exposure.
levels or if disease progression occurs (peripheral blast counts are           no dose re-escalation.                                                           4.4. Special Warnings and Special Precautions for Use                         (depending on the infusion fluid for dilution), equivalent to 0.7-7% of the     rate greater than supportive care.                                         Oral candidiasis              5 (6)          2 (2) Vascular disorders                                                      Dehydration                           8 (8)            • Sweet’s syndrome (acute febrile neutrophilic dermatosis).
increasing or bone marrow blast counts are worsening), the patient                                                                                              Myelosuppression                                                              WHO recommended maximum daily intake of 2 g sodium for an adult.
may be considered to be a non-responder and alternative therapeutic
• Recovery requiring more than 6, but less than 8 weeks – Decitabine-                                                                                                                                                                             Table 1 Adverse Events Reported in ≥ 5% of Patients in the                                                                      Petechiae                         32 (39)             13 (16)           Hyperglycemia                         6 (6)            • Differentiation syndrome Trima 50 mg/vial dosing to be delayed for up to 2 weeks and                  Myelosuppression and complications of myelosuppression, including             4.5. Interactions with Other Medicinal Products and Other Forms                                                                                            Sinusitis NOS                 4 (5)          2 (2) options to Decitabine-Trima 50 mg/vial should be considered.                                                                                                                                                                                                                                                                        decitabine 50 mg/vial Group and at a Rate Greater than                                                                       Pallor                            19 (23)             10 (12)                                                                  AML the dose reduced to 11 mg/m2 every 8 hours (33 mg/m2/day,                    infections and bleeding that occur in patients with MDS or AML may                   of Interaction 4.2.1 Treatment Regimen – Option 1                                                 99 mg/m2/cycle) upon restarting therapy.                                     be exacerbated with Decitabine-Trima 50 mg/vial treatment. Therefore,
Supportive Care in the Controlled Trial in MDS                  Bacteremia                    4 (5)          0 (0)                                                                              Hypokalemia                           12 (12)          Summary of the safety profile No formal clinical drug interaction studies with decitabine have been Decitabine-Trima 50 mg/vial is administered at a dose of 15 mg/m2                                                                                               patients are at increased risk for severe infections (due to any pathogen                                                                                                                                                                Injury, poisoning and procedural complications Hypotension NOS                   5 (6)               4 (5)             Hypomagnesemia                        5 (5)            The most common adverse drug reactions (≥ 35%) reported are body surface by continuous intravenous infusion over 3 hours repeated • Recovery requiring more than 8, but less than 10 weeks – the
Decitabine-Trima 50 mg/vial dose should be delayed up to 2 more weeks        such as bacterial, fungal and viral), with potentially fatal outcome (see conducted.
There is the potential for a drug-drug interaction with other agents decitabine
50 mg/vial
Supportive
Care                                                                    Hematoma NOS                      4 (5)               3 (4)             Musculoskeletal and connective tissue disorders pyrexia, anemia and thrombocytopenia.                                        Decitabine -Trima N = 83 (%)        N = 81 (%)
Transfusion reaction          6 (7)          3 (4)                                                                                                                                     The most common Grade 3/4 adverse drug reactions (≥ 20%) included every 8 hours for 3 days. This cycle should be repeated every 6 weeks Patients may be premedicated with standard anti-emetic therapy.
and the dose reduced to 11 mg/m2 every 8 hours (33 mg/m2/day,
99 mg/m2/cycle) upon restarting therapy, then maintained in section 4.8). Patients should be monitored for signs and symptoms of infection and treated promptly.
which are also activated by sequential phosphorylation (via intracellular phosphokinase activities) and/or metabolized by enzymes implicated                                                                                         Abrasion NOS                  4 (5)          1 (1) In a single-arm MDS study (N=99) decitabine 50 mg/vial was dosed at
20 mg/m2 intravenous, infused over one hour daily for 5 consecutive
Arthralgia                            17 (17)          pneumonia, thrombocytopenia, neutropenia, febrile neutropenia and               50 mg/vial 4.2.2 Treatment Regimen – Option 2                                                 subsequent cycles as clinically indicated.                                   In AML clinical studies, the majority of patients had baseline Grade 3/4                                                                                       Blood and lymphatic system disorders                                                                                                                                                                                                                             anaemia.
in the inactivation of decitabine (e.g., cytidine deaminase). Therefore,                                                                                   Investigations                                         days of a 4 week cycle. Table 2 presents all adverse events regardless   Back pain                             18 (18) Decitabine-Trima 50 mg/vial is administered at a dose of 20 mg/m2              • Recovery requiring more than 10 weeks – Patient should be                      myelosuppression. In patients with baseline Grade 2 abnormalities,            caution should be exercised if these active substances are combined              Neutropenia                        75 (90)           58 (72)                                                                     of causality occurring in at least 5% of patients.                                                                              In clinical studies, 30% of patients treated with decitabine 50 mg/vial Bone pain                             6 (6)            and 25% of patients treated in the comparator arm had adverse events              P00001568 0823B by continuous intravenous infusion over 1 hour repeated daily for 5                discontinued from the treatment of the drug and assessed for                 worsening of myelosuppression was seen in most patients and more              with Decitabine-Trima 50 mg/vial.                                                                                                                          Cardiac murmur NOS            13 (16)        9 (11) days. This cycle should be repeated every 4 weeks. Patients may be                 disease progression (by bone marrow aspirate) within 7 days after            frequently than in patients with baseline Grade 1 or 0 abnormalities.                                                                                          Thrombocytopenia                   74 (89)           64 (79)                                                                         Table 2 Adverse Events Reported in ≥ 5% of Patients in a                                                                    with an outcome of death during treatment or within 30 days after the Impact of co-administered medicinal products on decitabine                                                                                                 Blood alkaline phosphatase                                                       Single-arm Study*                              Muscle spasms                         7 (7)            last dose of study drug.
premedicated with standard anti-emetic therapy.                                    the end of 10 weeks. However, for patients who have been treated             Myelosuppression caused by Decitabine-Trima 50 mg/vial is reversible.         Cytochrome (CYP) 450-mediated metabolic interactions are not                     Anemia NOS                         68 (82)           60 (74)                                            9 (11)         7 (9) NOS increased