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
Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4
Metabolism and nutrition
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
Cough 23 (18) 0 10 (21) 0
Dyspnea 17 (13) 3 (2) 10 (21) 2 (4)
Weight decreased 14 (11) 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, 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 Warningsand 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.
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%).
6.2 Postmarketing Experience
No additional safety signals have been observed from postmarketing
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. 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.
7.2 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%.
Monitor for toxicity related to increased romidepsin exposure and follow
the dose modifications for toxicity [see Dosage and Administration(2.2)]
when romidepsin is initially co-administered with strong CYP3A4
inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
7.3 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. 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.
7.4 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
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category D [see Warnings and Precautions (5.5)].
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. 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.
Romidepsin was administered intravenously to rats during the period of
organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption
or post-implantation 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 folded retina, rotated limbs, and
incomplete sternal ossification.
8.3 Nursing Mothers
It is not known whether romidepsin is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from ISTODAX, a decision
should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of ISTODAX in pediatric patients has not been
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
No dedicated hepatic impairment study for ISTODAX has been conducted.
Mild hepatic impairment does not alter pharmacokinetics of romidepsin
based on a population pharmacokinetic analysis. Patients with moderate
and severe hepatic impairment should be treated with caution.
8.7 Renal Impairment
No dedicated renal impairment study for ISTODAX has been conducted.
Based upon the population pharmacokinetic analysis, renal impairment
is not expected to significantly influence drug exposure. The effect of
end-stage renal disease on romidepsin pharmacokinetics has not been
studied. Thus, patients with end-stage renal disease should be treated
No specific information is available on the treatment of overdosage of
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
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Summit, NJ 07901
Manufactured by: Ben Venue Laboratories, Inc.
Bedford, OH 44146
Baxter Oncology GmbH
ISTODAX® is a registered trademark of Celgene Corporation
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