"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
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 and ADVERSE REACTIONS].
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].
Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations [see ADVERSE REACTIONS]. 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.
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].
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 during treatment.
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 ma y be at greater risk, should be closely monitored, and managed as appropriate.
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].
Patient Counseling Information
See FDA-approved patient labeling.
- Nausea and Vomiting
Advise patients that nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended for all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [see ADVERSE REACTIONS].
- Low Blood Counts
Advise patients 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 [see WARNINGS AND PRECAUTIONS].
Advise patients that infections may occur during treatment with ISTODAX. Advise patients to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems. Advise patients to report any previous history of hepatitis B before starting romidepsin [see WARNINGS AND PRECAUTIONS].
- Tumor Lysis Syndrome
Advise patients of the risk of tumor lysis syndrome (especially those with advanced stage disease and/or high tumor burden) to maintain high fluid intake for at least 72 hours after each dose [see WARNINGS AND PRECAUTIONS].
- Use in Pregnancy
If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling [see WARNINGS AND PRECAUTIONS].
- Patients should be instructed to read the patient insert carefully.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m² in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.
Based on nonclinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m²/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m²/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m²/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m²/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m²/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m²/day). This dose is approximately 30% the estimated human daily dose based on body surface area.
Use In Specific Populations
Pregnancy Category D [see WARNINGS AND PRECAUTIONS].
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.
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.
The safety and effectiveness of ISTODAX in pediatric patients has not been established.
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.
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 [see CLINICAL PHARMACOLOGY].
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 with caution [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 11/3/2014
This monograph has been modified to include the generic and brand name in many instances.
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