WARNINGS AND PRECAUTIONS
Thromboembolism
As pulmonary embolism and deep vein thrombosis have been reported as adverse reactions, physicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events [see Adverse Reactions (6) ].
Hematologic
Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. If platelet counts and/or hemoglobin are reduced during treatment with ZOLINZA, the dose should be modified or therapy discontinued. [See Dosage and Administration, Warnings and Precautions and Adverse Reactions (6).]
Gastrointestinal
Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported [see Adverse Reactions (6) ] and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration [see Adverse Reactions]. Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with ZOLINZA.
Hyperglycemia
Hyperglycemia has been observed in patients receiving ZOLINZA [see Adverse Reactions]. Serum glucose should be monitored, especially in diabetic or potentially diabetic patients. Adjustment of diet and/or therapy for increased glucose may be necessary.
QTc Prolongation
A definitive study of the effect of vorinostat on QTc has not been conducted. Three of 86 CTCL patients exposed to 400 mg once daily had Grade 1 (>450-470 msec) or 2 (>470-500 msec or increase of >60 msec above baseline) clinical adverse events of QTc prolongation. In a retrospective analysis of three Phase 1 and two Phase 2 studies, 116 patients had a baseline and at least one follow-up ECG. Four patients had Grade 2 (>470-500 msec or increase of >60 msec above baseline) and 1 patient had Grade 3 (>500 msec) QTc prolongation. In 49 non-CTCL patients from 3 clinical trials who had complete evaluation of QT interval, 2 had QTc measurements of >500 msec and 1 had a QTc prolongation of >60 msec.
Monitoring: Laboratory Tests
Careful monitoring of blood cell counts and chemistry tests, including electrolytes, glucose and serum creatinine, should be performed every 2 weeks during the first 2 months of therapy and monthly thereafter. Electrolyte monitoring should include potassium, magnesium and calcium. Baseline and periodic ECGs should be performed during treatment. ZOLINZA should be administered with particular caution in patients with congenital long QT syndrome, and patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Hypokalemia or hypomagnesemia should be corrected prior to administration of ZOLINZA, and consideration should be given to monitoring potassium and magnesium in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms). [See Warnings and Precautions.]
Other Histone Deacetylase (HDAC) Inhibitors
Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks during the first 2 months. [See Drug Interactions].
Pregnancy
Pregnancy Category D
ZOLINZA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of ZOLINZA in pregnant women. Results of animal studies indicate that vorinostat crosses the placenta and is found in fetal plasma at levels up to 50% of maternal concentrations. Doses up to 50 and 150 mg/kg/day were tested in rats and rabbits, respectively (~0.5 times the human exposure based on AUC0-24 hours). Treatment-related developmental effects including decreased mean live fetal weights, incomplete ossifications of the skull, thoracic vertebra, sternebra, and skeletal variations (cervical ribs, supernumerary ribs, vertebral count and sacral arch variations) in rats at the highest dose of vorinostat tested. Reductions in mean live fetal weight and an elevated incidence of incomplete ossification of the metacarpals were seen in rabbits dosed at 150 mg/kg/day. The no observed effect levels (NOELs) for these findings were 15 and 50 mg/kg/day (<0.1 times the human exposure based on AUC) in rats and rabbits, respectively. A dose-related increase in the incidence of malformations of the gall bladder was noted in all drug treatment groups in rabbits versus the concurrent control. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [See Warnings and Precautions]
Nursing Mothers
It is not known whether this drug 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 ZOLINZA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of ZOLINZA in pediatric patients have not been established.
Geriatric Use
Of the total number of patients with CTCL in trials (N=107), 46 percent were 65 years of age and over, while 15 percent were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Use in Patients with Hepatic Impairment
Vorinostat was not evaluated in patients with hepatic impairment. As vorinostat is predominantly eliminated through metabolism, patients with hepatic impairment should be treated with caution. [See Clinical Pharmacology.]
Use in Patients with Renal Impairment
Vorinostat was not evaluated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. Patients with pre-existing renal impairment should be treated with caution. [See Clinical Pharmacology.]
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