Vorinostat

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# Overview
Vorinostat is a histone deacetylase inhibitor that is FDA approved 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.   Common adverse reactions include diarrhea, fatigue, nausea, thrombocytopenia, anorexia and dysgeusia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Vorinostat 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.
- Dosage: 400 mg orally once daily with food.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorinostat in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Vorinostat in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness not established in pediatric patients

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorinostat in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Vorinostat in pediatric patients.

# Contraindications
None

# Warnings
- Pulmonary embolism occurred in 5% (4/86) of patients receiving vorinostat, 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.
- Treatment with vorinostat 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 vorinostat as clinically appropriate.
- Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration. Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with vorinostat.
- Hyperglycemia has been observed in patients receiving vorinostat and was severe in 5% (4/86) of patients. Monitor serum glucose every 2 weeks during the first 2 months of therapy and monthly thereafter.
- 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 vorinostat. Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms).
- Severe thrombocytopenia leading to gastrointestinal bleeding has been reported with concomitant use of vorinostat and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently.

# Adverse Reactions

## Clinical Trials Experience
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.
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 vorinostat 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 vorinostat 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.
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 and fatigue were increased at doses higher than 400 mg once daily of vorinostat.
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.
Of the CTCL patients who received the 400-mg once daily dose, 9.3% (8/86) of patients discontinued vorinostat 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.
Of the CTCL patients who received the 400-mg once daily dose, 10.5% (9/86) of patients required a dose modification of vorinostat 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 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.
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.
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.
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  population included single events of blurred vision, asthenia, hyponatremia, tumor hemorrhage, Guillain-Barre syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension, and vasculitis.
In patients recovering from bowel surgery and treated perioperatively with vorinostat, anastomotic healing complications including fistulas, perforations, and abscess formation have occurred.

## Postmarketing Experience
There is limited information regarding Vorinostat Postmarketing Experience in the drug label.

# Drug Interactions

### Coumarin-Derivative Anticoagulants
- Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving vorinostat concomitantly with coumarin-derivative anticoagulants. Physicians should monitor PT and INR more frequently in patients concurrently administered vorinostat and coumarin derivatives.

### Other HDAC Inhibitors
- Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of vorinostat and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
Vorinostat can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of vorinostat 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vorinostat in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Vorinostat during labor and delivery.

### 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 vorinostat, 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 vorinostat in pediatric patients have not been established.

### Geriatic Use
Of the total number of patients with  in trials (N=107), 46 % were 65 years of age and over, while 15 % 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 should be considered, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

### Gender
Based upon an exploratory analysis of limited data, gender do not appear to have meaningful effects on the pharmacokinetics of vorinostat.

### Race
Based upon an exploratory analysis of limited data, race do not appear to have meaningful effects on the pharmacokinetics of vorinostat.

### 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.

### Hepatic Impairment
Vorinostat 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) 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 vorinostat in patients with bilirubin 1 to 3  ULN or AST > ULN.

### Females of Reproductive Potential and Males
Effects on the female reproductive system 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 were noted 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 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.

### Immunocompromised Patients
There is no FDA guidance one the use of Vorinostat in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Oral

### Monitoring
- 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 vorinostat.
- Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms).

# IV Compatibility
There is limited information regarding the compatibility of Vorinostat and IV administrations.

# Overdosage
- No specific information is available on the treatment of overdosage of vorinostat.
- In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known if vorinostat is dialyzable.

# Pharmacology

## 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.

## Structure
The empirical formula is C14H20N2O3. The molecular weight is 264.32 and the structural formula is:

## Pharmacodynamics
A randomized, partially-blind, placebo-controlled, 2-period crossover study was performed to assess the effects of a single 800-mg dose of vorinostat on the QTc interval in 24 patients with advanced cancer. This study was conducted to assess the impact of vorinostat on ventricular repolarization. The upper bound of the 90% confidence interval of the placebo-adjusted mean QTc interval change-from-baseline was less than 10 msec at every time point through 24 hours. Based on these study results, administration of a single supratherapeutic 800-mg dose of vorinostat does not appear to prolong the QTc interval in patients with advanced cancer; however the study did not include a positive control to demonstrate assay sensitivity. In the fasted state, oral administration of a single 800-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 8.65.7 Mhr and 1.70.67 M and 2.1 (0.5-6) hours, respectively.
In clinical studies in patients with CTCL, 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 reactions 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.

## Pharmacokinetics
The pharmacokinetics of vorinostat were evaluated in 23 patients with relapsed or refractory advanced cancer. After oral administration of a single 400-mg dose of vorinostat with a high-fat meal, the mean  standard deviation area under the curve (AUC) and peak serum concentration (Cmax) and the median (range) time to maximum concentration (Tmax) were 5.51.8 Mhr, 1.20.62 M and 4 (2-10) hours, respectively.
In the fasted state, oral administration of a single 400-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 4.21.9 Mhr and 1.20.35 M and 1.5 (0.5-10) hours, respectively. Therefore, oral administration of vorinostat with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state. However, these small effects are not expected to be clinically meaningful. In clinical trials of patients with , vorinostat was taken with food.
At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median Tmax of 6.02.0 Mhr, 1.20.53 M and 4 (0.5-14) hours, respectively.
Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 g/mL.
The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by -oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively.
In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).
Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 165.8% of vorinostat dose as the Oglucuronide of vorinostat, and 368.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 5213.3% of vorinostat dose. The mean terminal half-life (t12) was ~2.0 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.

## Nonclinical Toxicology
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).

# Clinical Studies
In two open-label clinical studies, patients with refractory  have been evaluated to determine their response rate to oral vorinostat. 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.
In an open-label, single-arm, multicenter non-randomized study, 74 patients with advanced CTCL were treated with vorinostat at a dose of 400 mg once daily. The primary endpoint was response rate to oral vorinostat 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 ) in all patients treated with vorinostat. 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 vorinostat.
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 vorinostat.
In an open-label, non-randomized study, vorinostat 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 7point 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).

# How Supplied
- Vorinostat capsules, 100 mg
- Bottle with 120 capsules.
- NDC 0006-0568-40.

## Storage
Store at 20-25C (68-77F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients should be instructed to drink at least 2 L/day of fluid to prevent dehydration and should promptly report excessive vomiting or diarrhea to their physician. Patients should be instructed about the signs of deep vein thrombosis and should consult their physician should any evidence of deep vein thrombosis develop. Patients receiving vorinostat should seek immediate medical attention if unusual bleeding occurs. vorinostat capsules should not be opened or crushed.
- Patients should be instructed to read the patient insert carefully.

# Precautions with Alcohol
Alcohol-Vorinostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Zolinza 

# Look-Alike Drug Names
There is limited information regarding Vorinostat Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price