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

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)].

5.2 Myelosuppression

Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. Adjust dosage or discontinue treatment with ZOLINZA as clinically appropriate [see Dosage and Administration (2.2), Warnings and Precautions (5.6) and 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 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, ZOLINZA can cause fetal harm when administered to a pregnant woman. There are insufficient data on ZOLINZA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, vorinostat crossed the placenta and caused adverse developmental outcomes at exposures approximately 0.5 times the human exposure based on AUC0-24 hours. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

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 evaluated 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.

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)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

ZOLINZA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of ZOLINZA in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ZOLINZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Use in Patients with Hepatic Impairment

ZOLINZA was studied in 42 patients with non-CTCL cancer and varying degrees of hepatic impairment after single and multiple-dose administration. Compared to patients with normal liver function, AUC increases of 50 to 66% were observed in patients with hepatic impairment. The incidence of Grade 3 or 4 thrombocytopenia increased in patients with mild (bilirubin of 1 to 1.5 × ULN and AST < ULN, or bilirubin ≤ ULN and AST > ULN) and moderate (bilirubin 1.5 to ≤ 3 × ULN) hepatic impairment treated daily at doses of 300 and 200 mg respectively.

Patients with severe hepatic impairment (bilirubin > 3 × ULN) have not been treated at doses greater than 200 mg a day. Reduce the initial dose of ZOLINZA in patients with bilirubin 1 to 3 × ULN or AST > ULN [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50<86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with vorinostat.

Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary (CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay).

Treatment-related effects on female reproduction were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose-dependent increases in corpora lutea were noted at ≥15 mg/kg/day, which resulted in increased peri-implantation losses at ≥50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions.

No effects on reproductive performance or fertility were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC) for 70 days prior to mating with untreated females.

Cutaneous T-cell Lymphoma

In two open-label clinical studies, patients with refractory CTCL have been evaluated to determine their response rate to oral ZOLINZA. One study was a single-arm clinical study and the other assessed several dosing regimens. In both studies, patients were treated until disease progression or intolerable toxicity.

Study 1

In an open-label, single-arm, multicenter non-randomized study (NCT00091559), 74 patients with advanced CTCL were treated with ZOLINZA at a dose of 400 mg once daily. The primary endpoint was response rate to oral ZOLINZA in the treatment of skin disease in patients with advanced CTCL (Stage IIB and higher) who had progressive, persistent, or recurrent disease on or following two systemic therapies. Enrolled patients should have received, been intolerant to or not a candidate for bexarotene. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool (SWAT). The investigator measured the percentage total body surface area (%TBSA) involvement separately for patches, plaques, and tumors within 12 body regions using the patient's palm as a "ruler". The total %TBSA for each lesion type was multiplied by a severity weighting factor (1=patch, 2=plaque and 4=tumor) and summed to derive the SWAT score. Efficacy was measured as either a Complete Clinical Response (CCR) defined as no evidence of disease, or Partial Response (PR) defined as a ≥50% decrease in SWAT skin assessment score compared to baseline. Both CCR and PR had to be maintained for at least 4 weeks.

Secondary efficacy endpoints included response duration, time to progression, and time to objective response.

The population had been exposed to a median of three prior therapies (range 1 to 12).

Table 2 summarizes the demographic and disease characteristics of the Study 1 population.

The overall objective response rate was 29.7% (22/74, 95% CI [19.7 to 41.5%]) in all patients treated with ZOLINZA. In patients with Stage IIB and higher CTCL, the overall objective response rate was 29.5% (18/61). One patient with Stage IIB CTCL achieved a CCR. Median times to response were 55 and 56 days (range 28 to 171 days), respectively in the overall population and in patients with Stage IIB and higher CTCL. However, in rare cases it took up to 6 months for patients to achieve an objective response to ZOLINZA.

The median response duration was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed 6 months for both the overall population and in patients with Stage IIB and higher CTCL. When end of response was defined as a 50% increase in SWAT score from the nadir, the estimated median response duration was 168 days and the median time to tumor progression was 202 days.

Using a 25% increase in SWAT score from the nadir as criterion for tumor progression, the estimated median time-to-progression was 148 days for the overall population and 169 days in the 61 patients with Stage IIB and higher CTCL.

Response to any previous systemic therapy does not appear to be predictive of response to ZOLINZA.

Study 2

In an open-label, non-randomized study, ZOLINZA was evaluated to determine the response rate for patients with CTCL who were refractory or intolerant to at least one treatment. In this study, 33 patients were assigned to one of 3 cohorts: Cohort 1, 400 mg once daily; Cohort 2, 300 mg twice daily 3 days/week; or Cohort 3, 300 mg twice daily for 14 days followed by a 7-day rest (induction). In Cohort 3, if at least a partial response was not observed then patients were dosed with a maintenance regimen of 200 mg twice daily. The primary efficacy endpoint, objective response, was measured by the 7-point Physician's Global Assessment (PGA) scale. The investigator assessed improvement or worsening in overall disease compared to baseline based on overall clinical impression. Index and non-index cutaneous lesions as well as cutaneous tumors, lymph nodes and all other disease manifestations were also assessed and included in the overall clinical impression. CCR required 100% clearing of all findings, and PR required at least 50% improvement in disease findings.

The median age was 67.0 years (range 26.0 to 82.0). Fifty-five percent of patients were male, and 45% of patients were female. Fifteen percent of patients had Stage IA, IB, or IIA CTCL and 85% of patients had Stage IIB, III, IVA, or IVB CTCL. The median number of prior systemic therapies was 4 (range 0.0 to 11.0).

In all patients treated, the objective response was 24.2% (8/33) in the overall population, 25% (7/28) in patients with Stage IIB or higher disease and 36.4% (4/11) in patients with Sezary syndrome. The overall response rates were 30.8%, 9.1% and 33.3% in Cohort 1, Cohort 2 and Cohort 3, respectively. The 300 mg twice daily regimen had higher toxicity with no additional clinical benefit over the 400 mg once daily regimen. No CCR was observed.

Among the 8 patients who responded to study treatment, the median time to response was 83.5 days (range 25 to 153 days). The median response duration was 106 days (range 66 to 136 days). Median time to progression was 211.5 days (range 94 to 255 days).

Storage and Handling

Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

ZOLINZA (vorinostat) capsules should not be opened or crushed. Direct contact of the powder in ZOLINZA capsules with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed and/or broken capsules [see Nonclinical Toxicology (13.1)].

Embryo-Fetal Toxicity

Advise patients that ZOLINZA can cause fetal harm when administered during pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment with ZOLINZA and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception and to avoid fathering a child during treatment with ZOLINZA and for at least 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise lactating women not to breastfeed during treatment with ZOLINZA and for at least 1 week after the last dose [see Use in Specific Populations (8.2)].