Special Warning : אזהרת שימוש

5   WARNINGS AND PRECAUTIONS

5.1   Myelosuppression
Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with ISTODAX and modify the dose as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

5.2   Infections
Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow [see Adverse Reactions (6.1)].
Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations [see Adverse Reactions (6.1)]. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis.
Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.

5.3   Electrocardiographic Changes
Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [see Adverse Reactions (6.1)].
In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.
Confirm that potassium and magnesium levels are within normal range before administration of ISTODAX [see Adverse Reactions (6.1)].

5.4   Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden are at greater risk, should be closely monitored, and managed as appropriate.

5.5   Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, ISTODAX can cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and caused adverse developmental outcomes at exposures below those in patients at the recommended dose of 14 mg/m2. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (11.1)].

6   ADVERSE REACTIONS
The following adverse reactions are described in more detail in other sections of the prescribing information.
•    Myelosuppression [see Warnings and Precautions (5.1)]
•    Infections [see Warnings and Precautions (5.2)]
•    Electrocardiographic Changes [see Warnings and Precautions (5.3)] •    Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]

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.
Cutaneous T-Cell Lymphoma
The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions
Table 1 summarizes the most frequent adverse reactions (>20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (>20%) as adverse reactions are included in Table 1.
                                                                  Table 1. Adverse Reactions
Occurring in >20% of Patients in Either CTCL Study (N=185)

Study 1                                         Study 2
(n=102)                                         (n=83)
Adverse Reactions n (%)                                                    All grades            Grade 3 or 4             All grades             Grade 3 or 4 Any adverse reactions                                                        99 (97)                 36 (35)               83 (100)                 68 (82) Nausea                                                                       57 (56)                  3 (3)                71 (86)                   5 (6) Asthenia/Fatigue                                                             54 (53)                  8 (8)                 64 (77)                 12 (14) Infections                                                                   47 (46)                 11 (11)                45 (54)                 27 (33) Vomiting                                                                     35 (34)                 1 (<1)                 43 (52)                  8 (10) Anorexia                                                                     23 (23)                 1 (<1)                 45 (54)                  3 (4) Hypomagnesemia                                                               22 (22)                 1 (<1)                 23 (28)                    0 Diarrhea                                                                     20 (20)                 1 (<1)                 22 (27)                  1 (1) Pyrexia                                                                      20 (20)                  4 (4)                 19 (23)                  1 (1) Anemia                                                                       19 (19)                  3 (3)                 60 (72)                 13 (16) Thrombocytopenia                                                             17 (17)                    0                   54 (65)                 12 (14) Dysgeusia                                                                    15 (15)                    0                   33 (40)                    0 Constipation                                                                 12 (12)                  2 (2)                 32 (39)                  1 (1) Neutropenia                                                                  11 (11)                  4 (4)                 47 (57)                 22 (27) Hypotension                                                                   7 (7)                   3 (3)                 19 (23)                  3 (4) Pruritus                                                                      7 (7)                     0                   26 (31)                  5 (6) Hypokalemia                                                                   6 (6)                     0                   17 (20)                  2 (2) Dermatitis/Exfoliative dermatitis                                             4 (4)                  1 (<1)                 22 (27)                  7 (8) Hypocalcemia                                                                  4 (4)                     0                   43 (52)                  5 (6) Leukopenia                                                                    4 (4)                     0                   38 (46)                 18 (22) Lymphopenia                                                                   4 (4)                     0                   47 (57)                 31 (37) Alanine aminotransferase increased                                            3 (3)                     0                   18 (22)                  2 (2) Aspartate aminotransferase increased                                          3 (3)                     0                   23 (28)                  3 (4) Hypoalbuminemia                                                               3 (3)                  1 (<1)                 40 (48)                  3 (4) Electrocardiogram ST-T wave changes                                           2 (2)                     0                   52 (63)                    0 Hyperglycemia                                                                 2 (2)                   2 (2)                 42 (51)                  1 (1) Hyponatremia                                                                 1 (<1)                  1 (<1)                 17 (20)                  2 (2) Hypermagnesemia                                                                 0                       0                   22 (27)                  7 (8) Hypophosphatemia                                                                0                       0                   22 (27)                  8 (10) Hyperuricemia                                                                   0                       0                   27 (33)                  7 (8) 
Serious Adverse Reactions
Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in >2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in >2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).
There were eight deaths not due to disease progression. In Study 1, there were two deaths: one due to cardiopulmonary failure and one due to acute renal failure. There were six deaths in Study 2: four due to infection , and one each due to myocardial ischemia and acute respiratory distress syndrome.

Discontinuations
Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.


Peripheral T-Cell Lymphoma
The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4.

Common Adverse Reactions
Table 2 summarizes the most frequent adverse reactions (≥10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥10%) as adverse reactions are included in Table 2.
Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) 
Study 3                                              Study 4
(N=131)                                              (N=47)
Adverse Reactions n (%)                                           All grades               Grade 3 or 4               All grades                 Grade 3 or 4 Any adverse reactions                                              128 (97)                  88 (67)                   47 (100)                    40 (85) Gastrointestinal disorders
Nausea                                                           77 (59)                    3 (2)                    35 (75)                     3 (6) Vomiting                                                         51 (39)                    6 (5)                    19 (40)                     4 (9) Diarrhea                                                         47 (36)                    3 (2)                    17 (36)                     1 (2) Constipation                                                     39 (30)                   1 (<1)                    19 (40)                     1 (2) Abdominal pain                                                   18 (14)                    3 (2)                    6 (13)                      1 (2) Stomatitis                                                       14 (11)                      0                       3 (6)                        0 General disorders and administration site conditions
Asthenia/Fatigue                                                 72 (55)                   11 (8)                    36 (77)                     9 (19) Pyrexia                                                          46 (35)                    8 (6)                    22 (47)                     8 (17) Chills                                                           14 (11)                   1 (<1)                    8 (17)                         0 Edema peripheral                                                 13 (10)                   1 (<1)                     3 (6)                         0 Blood and lymphatic system disorders
Thrombocytopenia                                                 53 (41)                   32 (24)                   34 (72)                    17 (36) Neutropenia                                                      39 (30)                   26 (20)                   31 (66)                    22 (47) Anemia                                                           33 (25)                   14 (11)                   29 (62)                    13 (28) Leukopenia                                                       16 (12)                    8 (6)                    26 (55)                    21 (45) Metabolism and nutrition disorders
Anorexia                                                         37 (28)                    2 (2)                    21 (45)                     1 (2) Hypokalemia                                                      14 (11)                    3 (2)                    8 (17)                      1 (2) Nervous system disorders
Dysgeusia                                                        27 (21)                      0                      13 (28)                       0 Headache                                                         19 (15)                      0                      16 (34)                     1 (2) Respiratory, thoracic and mediastinal disorders
Cough                                                            23 (18)                      0                      10 (21)                       0 Dyspnea                                                          17 (13)                    3 (2)                    10 (21)                     2 (4) Investigations
Weight decreased                                                 14 (11)                      0                       7 (15)                       0 Cardiac disorders
Tachycardia                                                      13 (10)                      0                         0                          0 
Serious Adverse Reactions
Infections were the most common type of SAE reported. In Study 3, twenty-six patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, eleven patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.
Serious adverse reactions reported in ≥2% of patients in Study 3 were pyrexia (8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).
Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL in clinical trials in Western populations enrolled in Study 3 and Study 4 [see Warnings and Precautions (5.2)].
Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.
Discontinuations
Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

Reporting suspected adverse reactions after authorization 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 /and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com 7    DRUG INTERACTIONS

7.1    Warfarin or Coumarin Derivatives
Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin [see Clinical Pharmacology (12.3)].

7.2    Drugs That Inhibit CYP3A4 Enzymes
Strong CYP3A4 inhibitors increase concentrations of romidepsin. [see Clinical Pharmacology (12.3)]. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when ISTODAX is initially co-administered with strong CYP3A4 inhibitors 
7.3    Drugs That Induce CYP3A4 Enzymes
Rifampin (a potent CYP3A4 inducer) increased the concentrations of romidepsin [see Clinical Pharmacology (12.3)]. Avoid co-administration of ISTODAX with rifampin.
The use of other potent CYP3A4 inducers should be avoided when possible.

8    USE IN SPECIFIC POPULATIONS

8.1    Pregnancy
Risk Summary
Based on its mechanism of action and findings from animal studies, ISTODAX can cause embryo-fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
There are no available data on ISTODAX use in pregnant women to inform a drug associated risk of major birth defects and miscarriage. In an animal reproductive study, romidepsin was embryocidal and caused adverse developmental outcomes including embryo-fetal toxicity and malformations at exposures below those in patients at the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus and to avoid becoming pregnant while receiving ISTODAX, and for at least 1 month after the last dose.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
Data
Animal Data
Romidepsin was administered intravenously to pregnant rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or postimplantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of reduced fetal body weights, folded retina, rotated limbs, and incomplete sternal ossification.

8.2    Lactation
Risk Summary
There are no data on the presence of ISTODAX or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with ISTODAX and for at least 1 week after the last dose.

8.3   Females and Males of Reproductive Potential
ISTODAX can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].
Pregnancy Testing
Perform pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with ISTODAX.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with ISTODAX and for at least 1 month after the last dose. ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. Therefore, alternative methods of non-estrogen containing contraception (e.g., condoms, intrauterine devices) should be used in patients receiving ISTODAX.
Males
Advise males with female partners of reproductive potential to use effective contraception and to avoid fathering a child during treatment with ISTODAX and for at least 1 month after the last dose.
Infertility
Based on findings in animals, romidepsin has the potential to affect male and female fertility [see Nonclinical Toxicology (13.1)].

8.4    Pediatric Use
The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5    Geriatric Use
Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6    Hepatic Impairment
In a hepatic impairment study, ISTODAX was evaluated in 19 patients with advanced cancer and mild (8), moderate (5), or severe (6) hepatic impairment There were 4 deaths during the first cycle of treatment: 1 patient with mild hepatic impairment 1 patient with moderate hepatic impairment, and 2 patients with severe hepatic Impairment. The use of ISTODAX is not recommended in patients with severe hepatic impairment. No dose adjustments are recommended for patients with mild hepatic impairment. Reduce the ISTODAX starting dose for patients with moderate hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (11.3)]. Monitor patients with hepatic impairment more frequently for toxicity, especially during the first cycle of therapy.

9    OVERDOSAGE
No specific information is available on the treatment of overdosage of ISTODAX.
Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2-fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

10    DESCRIPTION
Romidepsin, a histone deacetylase (HDAC) inhibitor, is a bicyclic depsipeptide. At room temperature, romidepsin is a white powder and is described chemically as (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone. The empirical formula is C24H36N4O6S2.
The molecular weight is 540.71 and the structural formula is:
H
O
CH3 HN                    CH3
S HN
H3C            O S
H
O       NH
HN       O
H
O                CH3

H        O        CH3

ISTODAX (romidepsin) for injection is intended for intravenous infusion only after reconstitution with the supplied diluent and after further dilution with 0.9% Sodium Chloride, USP.
ISTODAX is supplied as a kit containing 2 vials.
ISTODAX (romidepsin) for injection is a sterile lyophilized white powder and is supplied in a 10 mg single-dose vial containing 11 mg romidepsin and 22 mg povidone, USP, and hydrochloric acid, NF, as a pH adjuster..
Diluent for ISTODAX is a sterile clear solution and is supplied in a single-dose vial containing 2.4 mL (2.2 mL deliverable volume). Diluent for ISTODAX contains 80% (v/v) propylene glycol, USP and 20% (v/v) dehydrated alcohol, USP.

11    CLINICAL PHARMACOLOGY

11.1 Mechanism of Action
Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

11.2 Pharmacodynamics
Cardiac Electrophysiology
At doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8 (0.57 times the recommended dose), 10 (0.71 times the recommended dose) or 12 (0.86 times the recommended dose) mg/m2 as a 1-hour infusion, no large changes in the mean QTc interval (>20 milliseconds) from baseline based on Fridericia correction method were detected. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded.
Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6-hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion.

11.3 Pharmacokinetics

In patients with T-cell lymphomas who received 14 mg/m2 of romidepsin intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-∞) were 377 ng/mL and 1549 ng*hr/mL, respectively. Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 (0.07 times the recommended dose) to 24.9 (1.76 times the recommended dose) mg/m2 when administered intravenously over 4 hours in patients with advanced cancers.

Distribution
Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1).
In vitro, romidepsin accumulates into human hepatocytes via an unknown active uptake process. Romidepsin is not a substrate of the following uptake transporters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. In addition, romidepsin is not an inhibitor of BCRP, MRP2, MDR1 or OAT3. Although romidepsin did not inhibit OAT1, OCT2, and OATP1B3 at concentrations seen clinically (1 μmol/L), modest inhibition was observed at 10 μmol/L. Romidepsin was found to be an inhibitor of BSEP and OATP1B1.

Metabolism
Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro.
At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4 in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when co-administered with CYP450 substrates.

Excretion
Following 4-hour intravenous administration of romidepsin at 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle in patients with T-cell lymphomas, the terminal half-life (t1/2) was approximately 3 hours. No accumulation of plasma concentration of romidepsin was observed after repeated dosing.

Effects on Driving