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ZOLINZA (vorinostat) Capsules
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ZOLINZA safely and effectively. See full prescribing information for ZOLINZA.
ZOLINZA ® (vorinostat) Capsules
Initial U.S. Approval: 2006
RECENT MAJOR CHANGES
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Dosage and Administration |
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Dose Modifications (2.2) |
04/2013 |
INDICATIONS AND USAGE
ZOLINZA is a histone deacetylase (HDAC) inhibitor indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. (1)
DOSAGE AND ADMINISTRATION
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400 mg orally once daily with food. (2.1)
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If patient is intolerant to therapy, reduce the dose to 300 mg orally once daily with food. If necessary, reduce the dose further to 300 mg once daily with food for 5 consecutive days each week. (2.2, 5)
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Reduce dose in patients with mild or moderate hepatic impairment. (2.2)
DOSAGE FORMS AND STRENGTHS
None (4)
WARNINGS AND PRECAUTIONS
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Pulmonary embolism and deep vein thrombosis: Monitor for pertinent signs and symptoms. (5.1)
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Thrombocytopenia and anemia: May require dose modification or discontinuation. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. (2.2, 5.2, 6)
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Gastrointestinal Toxicity: Nausea, vomiting and diarrhea; patients may require antiemetics, antidiarrheals, and fluid and electrolyte replacement to prevent dehydration. (5.3, 6, 17.1)
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Hyperglycemia: Monitor blood glucose every 2 weeks during the first 2 months of therapy and monthly thereafter. (5.4)
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Clinical chemistry abnormalities: Measure and correct abnormal electrolytes, creatinine, magnesium and calcium at baseline. Monitor every 2 weeks during the first 2 months of therapy and at least monthly during treatment. (5.5)
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Severe thrombocytopenia with gastrointestinal bleeding has been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently. (5.6, 7.2)
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Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus. (5.7)
ADVERSE REACTIONS
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The most common adverse reactions (incidence ≥20%) are diarrhea, fatigue, nausea, thrombocytopenia, anorexia and dysgeusia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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Coumarin-derivative anticoagulants: Prolongation of prothrombin time and International Normalized Ratio (INR) have been observed with concomitant use. Monitor INR frequently. (7.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 4/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ZOLINZA® is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
The recommended dose is 400 mg orally once daily with food.
Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
ZOLINZA capsules should not be opened or crushed [see How Supplied/Storage and Handling (16)].
2.2 Dose Modifications
If a patient is intolerant to therapy, the dose may be reduced to 300 mg orally once daily with food. The dose may be further reduced to 300 mg once daily with food for 5 consecutive days each week, as necessary.
Hepatic Impairment
Reduce the starting dose to 300 mg orally once daily with food in patients with mild to moderate hepatic impairment (bilirubin 1 to 3 × ULN or AST > ULN). There is insufficient evidence to recommend a starting dose for patients with severe hepatic impairment (bilirubin > 3 × ULN). [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
100 mg white, opaque, hard gelatin capsules with "568" over "100 mg" printed within radial bar in black ink on the capsule body.
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Thromboembolism
Pulmonary embolism occurred in 5% (4/86) of patients receiving ZOLINZA, and deep vein thrombosis has also been reported. Monitor for signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events [see Adverse Reactions (6)].
5.3 Gastrointestinal Toxicity
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 (6.1)]. Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with ZOLINZA.
5.4 Hyperglycemia
Hyperglycemia has been observed in patients receiving ZOLINZA and was severe in 5% (4/86) of patients [see Adverse Reactions (6.1)]. Monitor serum glucose every 2 weeks during the first 2 months of therapy and monthly thereafter.
5.5 Clinical Chemistry Abnormalities
Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. Correct hypokalemia and hypomagnesemia prior to administration of ZOLINZA. Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms).
5.6 Severe thrombocytopenia when combined with other Histone Deacetylase (HDAC) Inhibitors
Severe thrombocytopenia leading to gastrointestinal bleeding has been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently. [See Drug Interactions (7.2)].
5.7 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.
6 ADVERSE REACTIONS
The following serious adverse reactions have been associated with ZOLINZA in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions (5)].
Thromboembolism [see Warnings and Precautions (5.1)]
Myelosuppression [see Warnings and Precautions (5.2)]
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]
Hyperglycemia [see Warnings and Precautions (5.4)]
Clinical Chemistry Abnormalities [see Warnings and Precautions (5.5)]
Severe thrombocytopenia when combined with other Histone Deacetylase (HDAC) Inhibitors [see Warnings and Precautions (5.6)]
The most common drug-related adverse reactions can be classified into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation), constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia), and taste disorders (dysgeusia, dry mouth). The most common serious drug-related adverse reactions were pulmonary embolism and anemia.
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.
The safety of ZOLINZA was eva luated in 107 CTCL patients in two single arm clinical studies in which 86 patients received 400 mg once daily.
The data described below reflect exposure to ZOLINZA 400 mg once daily in the 86 patients for a median number of 97.5 days on therapy (range 2 to 480+ days). Seventeen (19.8%) patients were exposed beyond 24 weeks and 8 (9.3%) patients were exposed beyond 1 year. The population of CTCL patients studied was 37 to 83 years of age, 47.7% female, 52.3% male, and 81.4% white, 16.3% black, and 1.2% Asian or multi-racial.
Common Adverse Reactions
Table 1 summarizes the frequency of CTCL patients with specific adverse reactions, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0).
The frequencies of more severe thrombocytopenia, anemia [see Warnings and Precautions (5.2)] and fatigue were increased at doses higher than 400 mg once daily of ZOLINZA.
Serious Adverse Reactions
The most common serious adverse reactions in the 86 CTCL patients in two clinical trials were pulmonary embolism reported in 4.7% (4/86) of patients, squamous cell carcinoma reported in 3.5% (3/86) of patients and anemia reported in 2.3% (2/86) of patients. There were single events of cholecystitis, death (of unknown cause), deep vein thrombosis, enterococcal infection, exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobar pneumonia, myocardial infarction, ischemic stroke, pelviureteric obstruction, sepsis, spinal cord injury, streptococcal bacteremia, syncope, T-cell lymphoma, thrombocytopenia and ureteric obstruction.
Discontinuations
Of the CTCL patients who received the 400-mg once daily dose, 9.3% (8/86) of patients discontinued ZOLINZA due to adverse reactions. These adverse reactions, regardless of causality, included anemia, angioneurotic edema, asthenia, chest pain, exfoliative dermatitis, death, deep vein thrombosis, ischemic stroke, lethargy, pulmonary embolism, and spinal cord injury.
Dose Modifications
Of the CTCL patients who received the 400-mg once daily dose, 10.5% (9/86) of patients required a dose modification of ZOLINZA due to adverse reactions. These adverse reactions included increased serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia and vomiting. The median time to the first adverse reactions resulting in dose reduction was 42 days (range 17 to 263 days).
Laboratory Abnormalities
Laboratory abnormalities were reported in all of the 86 CTCL patients who received the 400-mg once-daily dose.
Increased serum glucose was reported as a laboratory abnormality in 69% (59/86) of CTCL patients who received the 400-mg once daily dose; only 4 of these abnormalities were severe (Grade 3). Increased serum glucose was reported as an adverse reaction in 8.1% (7/86) of CTCL patients who received the 400-mg once daily dose. [See Warnings and Precautions (5.4).]
Transient increases in serum creatinine were detected in 46.5% (40/86) of CTCL patients who received the 400-mg once daily dose. Of these laboratory abnormalities, 34 were NCI CTCAE Grade 1, 5 were Grade 2, and 1 was Grade 3.
Proteinuria was detected as a laboratory abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown.
Dehydration
Based on reports of dehydration as a serious drug-related adverse reaction in clinical trials, patients were instructed to drink at least 2 L/day of fluids for adequate hydration. [See Warnings and Precautions (5.3, 5.5).]
Adverse Reactions in Non-CTCL Patients
The frequencies of individual adverse reactions were substantially higher in the non-CTCL population. Drug-related serious adverse reactions reported in the non-CTCL population which were not observed in the CTCL population included single events of blurred vision, asthenia, hyponatremia, tumor hemorrhage, Guillain-Barré syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension, and vasculitis.
In patients recovering from bowel surgery and treated perioperatively with ZOLINZA, anastomotic healing complications including fistulas, perforations, and abscess formation have occurred.
7 DRUG INTERACTIONS
7.1 Coumarin-Derivative Anticoagulants
Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should monitor PT and INR more frequently in patients concurrently administered ZOLINZA and coumarin derivatives.
7.2 Other 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 for the first 2 months. [See Warnings and Precautions (5.6).]
8 USE IN SPECIFIC POPULATIONS
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