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Istodax

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Istodax

Side Effects
Interactions

SIDE EFFECTS

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 Grade 3 or 4 All 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/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%).

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 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 in these studies were 5.6 months and 6 cycles.

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 Grade 3 or 4 All Grade 3 or 4
Any adverse reactions Gastrointestinal disorders 127 (97) 86 (66) 47 (100) 40 (85)
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 General disorders and administration site conditions 13 (10) 0 3 (6) 0
Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19)
Pyrexia 46 (35) 7 (5) 22 (47) 8 (17)
Chills 14 (11) 1 ( < 1) 8 (17) 0
Edema peripheral Blood and lymphatic system disorders 13 (10) 1 ( < 1) 3 (6) 0
Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36)
Neutropenia 39 (30) 26 (20) 31 (66) 22 (47)
Anemia 32 (24) 14 (11) 29 (62) 13 (28)
Leukopenia Metabolism and nutrition disorders 16 (12) 8 (6) 26 (55) 21 (45)
Anorexia 37 (28) 2 (2) 21 (45) 1 (2)
Hypokalemia Nervous system disorders 14 (11) 3 (2) 8 (17) 1 (2)
Dysgeusia 27 (21) 0 13 (28) 0
Headache Respiratory, thoracic and mediastinal disorders 19 (15) 0 16 (34) 1 (2)
Cough 23 (18) 0 10 (21) 0
Dyspnea Investigations 17 (13) 3 (2) 10 (21) 2 (4)
Weight decreased Cardiac disorders 13 (10) 0 7 (15) 0
Tachycardia 13 (10) 0 0 0

Serious Adverse Reactions

Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) 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 (7%), 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%).

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

Coumadin or Coumadin 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 Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [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: 6/28/2013
This monograph has been modified to include the generic and brand name in many instances.

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