Dosing

• The recommended dose of ISTODAX is 14 mg/m² given 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 the patient continues to benefit from and tolerates
  the therapy

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Dose Modifications

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Drug Interactions

• ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers, if possible
  • Strong CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole
  • Potent CYP3A4 inducers: dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital
  • Patients should refrain from taking St. John’s Wort
• Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors
• Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives

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Use in Specific Populations

• Pregnancy: Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. 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 (Pregnancy Category D)
• 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
• Hepatic/Renal Impairment: Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

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Instructions for Patient Counseling

• Nausea and Vomiting
  Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted
• Low Blood Counts
  Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding
• Infections
  Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems
• Tumor Lysis Syndrome
  Patients at risk of tumor lysis syndrome (i.e., those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed
• Use in Women of Childbearing Potential
  If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling
  ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives
• Patients should be instructed to read the patient insert carefully

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ISTODAX^® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information

WARNINGS AND PRECAUTIONS:

• Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary
• Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy
• Electrocardiographic (ECG) changes have been observed with ISTODAX
• In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment
• Ensure that potassium and magnesium are within the normal range before administration of ISTODAX
• Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate
• ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. 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 (Pregnancy Category D)

ADVERSE REACTIONS:

Cutaneous T-Cell Lymphoma

The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (N=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (N=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (N=102) and Study 2 (N=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (N=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (N=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS:

• ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible
• Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors
• Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives

USE IN SPECIFIC POPULATIONS:

• 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
• Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

Please see full Prescribing Information, including, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

ISTODAX^® is a registered trademark of Celgene Corperation.
Celgene Patient Support^® is a registered trademark of Celgene Corporation.

©2009 year of origin. ©2011 date of revision. Celgene Corporation, www.celgene.com.
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