ISTODAX® (romidepsin) for injection
For intravenous infusion only
The following is a Brief Summary only; see full Prescribing Information for
complete product information.
1 INDICATIONS AND USAGE
ISTODAX is indicated for:
• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have
received at least one prior therapy.
These indications are based on response rate. Clinical benefit such as
improvement in overall survival has not been demonstrated.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
The recommended dose of romidepsin is 14 mg/m2 administered
intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle.
Cycles should be repeated every 28 days provided that the patient
continues to benefit from and tolerates the drug.
2. 2 Dose Modification
Nonhematologic toxicities except alopecia
• Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until
toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted
at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin
should be delayed until toxicity returns to ≤ Grade 1 or baseline and the
dose should be permanently reduced to 10 mg/m2.
• Grade 4 toxicity: Treatment with romidepsin should be delayed until
toxicity returns to ≤ Grade 1 or baseline, then the dose should be
permanently reduced to 10 mg/m2.
• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after
• Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with
romidepsin should be delayed until the specific cytopenia returns to
ANC ≥1.5×109/L and platelet count ≥ 75×109/L or baseline, then therapy
may be restarted at 14 mg/m2.
• Grade 4 febrile (≥ 38. 5°C) neutropenia or thrombocytopenia that
requires platelet transfusion: Treatment with romidepsin should be
delayed until the specific cytopenia returns to ≤ Grade 1 or baseline,
and then the dose should be permanently reduced to 10 mg/m2.
2. 3 Instructions for Preparation and Intravenous Administration
ISTODAX is a cytotoxic drug. Use appropriate handling procedures.
ISTODAX must be reconstituted with the supplied diluent and further
diluted with 0.9% Sodium Chloride Injection, USP before intravenous
• Each 10 mg single-use vial of ISTODAX (romidepsin) must be
reconstituted with 2 mL of the supplied diluent. With a suitable syringe,
aseptically withdraw 2 mL from the supplied diluent vial, and slowly
inject it into the ISTODAX (romidepsin) for injection vial. Swirl the
contents of the vial until there are no visible particles in the resulting
solution. The reconstituted solution will contain ISTODAX 5 mg/mL.
The reconstituted ISTODAX solution is chemically stable for up to
8 hours at room temperature.
• Extract the appropriate amount of ISTODAX from the vials to deliver the
desired dose, using proper aseptic technique. Before intravenous
infusion, further dilute ISTODAX in 500 mL 0.9% Sodium Chloride
• Infuse over 4 hours.
The diluted solution is compatible with polyvinyl chloride (PVC), ethylene
vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles,
and is chemically stable for up to 24 hours when stored at room temperature.
However, it should be administered as soon after dilution as possible.
Parenteral drug products should be inspected visually for particulate
matter and discoloration before administration, whenever solution and
5 WARNINGS AND PRECAUTIONS
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)].
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)].
Reactivation of hepatitis B virus infection has occurred in 1% of PTCL
patients in clinical trials in Western populations [see Adverse Reactions
( 6)]. 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)].
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
Confirm that potassium and magnesium levels are within normal range
before administration of ISTODAX [see Adverse Reactions ( 6)].
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 may be at greater
risk, should be closely monitored, and managed as appropriate.
5. 5 Use in Pregnancy
There are no adequate and well-controlled studies of ISTODAX in pregnant
women. However, based on its mechanism of action and findings in
animals, ISTODAX may cause fetal harm when administered to a pregnant
woman. In an animal reproductive study, romidepsin was embryocidal
and resulted in adverse effects on the developing fetus at exposures below
those in patients at the recommended dose of 14 mg/m2/week. If this drug
is used during pregnancy, or if the patient becomes pregnant while taking
ISTODAX, the patient should be apprised of the potential hazard to the
fetus [see Use in Specific Populations ( 8.1)].
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)]
• Infection [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.
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)
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
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
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)