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Istodax

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Istodax

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are described in more detail in other sections of the prescribing information.

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)

Adverse Reactions n (%) Study 1
(n=102)
Study 2
(n=83)
All grades Grade 3 or 4 All grades Grade 3 or 4
Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82)
Nausea 57 (56) 3 (3) 71 (86) 5 (6)
Asthenia/F atigue 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%), su praventricular 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%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), 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 stu dy 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)

Adverse Reactions n (%) Study 3
(N=131)
Study 4
(N=47)
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, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 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 patients in clinical trials in Western population enrolled in Study 3 and Study 4 [see WARNINGS AND PRECAUTIONS].

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%).

Postmarketing Experience

No additional safety signals have been observed from postmarketing experience.

Read the Istodax (romidepsin for injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Warfarin Or Coumarin Derivatives

Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin [see CLINICAL PHARMACOLOGY].

Drugs That Inhibit Cytochrome P450 3A4 Enzymes

Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25% [see CLINICAL PHARMACOLOGY].

Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see DOSAGE AND ADMINISTRATION] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

Drugs That Induce Cytochrome P450 3A4 Enzymes

Avoid co-administration of ISTODAX with rifampin.

In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively [see CLINICAL PHARMACOLOGY]. Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin's inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX.

It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John's Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

Drugs That Inhibit Drug Transport Systems

Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

Read the Istodax Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 11/3/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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