Vorinostat, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1, 2, 3
Vorinostat is used for the treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease during or after 2 prior systemic therapies.1, 2, 5, 6, 8 Vorinostat is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.7
Efficacy of vorinostat was evaluated in 2 open-label clinical trials in patients with refractory CTCL.1, 5, 6 In one multicenter study, 74 patients with CTCL who had received at least 2 prior systemic therapies, including bexarotene (unless the patient was not a candidate for or did not tolerate the drug), received vorinostat 400 mg orally once daily.1, 5 Most (82%) of the patients had stage IIB or more advanced disease.1, 5 Extent of disease was assessed using a modified Severity Weighted Assessment Tool (SWAT); complete clinical response was defined as no evidence of skin disease, and partial response was defined as a decrease of at least 50% from baseline in SWAT skin assessment score, with the respective response lasting at least 4 weeks.1, 5 An overall objective response was reported in about 30% of patients receiving vorinostat.1, 5 One patient with stage IIB CTCL achieved a complete clinical response.1 Median time to response was 55 days;1, 5 however, in rare cases, up to 6 months of treatment was required to achieve an objective response.1 Median response duration was not reached but was estimated to exceed 6 months.1, 5 Estimated median duration of response, with end of response defined as a 50% increase in SWAT score from the nadir, was 168 days, and median time to tumor progression was 202 days.1 Estimated median time to progression, with tumor progression defined as a 25% increase in SWAT score from the nadir, was 148 days for the overall population and 169 days for the 61 patients with stage IIB or more advanced CTCL.1 Response to prior systemic therapy did not appear to be predictive of response to vorinostat.1, 5
In a second open-label trial, 33 patients with CTCL refractory to at least one prior systemic therapy received one of the following oral vorinostat dosage regimens: 400 mg once daily (regimen 1); 300 mg twice daily 3 times weekly (regimen 2); or 300 mg twice daily for 14 days (induction therapy) followed by a 7-day rest and then, in those who had not achieved at least a partial response (defined as improvement in disease findings of at least 50% from baseline), maintenance therapy with vorinostat 200 mg twice daily (regimen 3).1, 6 Extent of disease was assessed using the 7-point Physician's Global Assessment (PGA) scale.1, 6 Overall objective response rates of about 24, 25, and 36%, respectively, were reported in the overall patient population, the 28 patients with stage IIB or more advanced disease, and the 11 patients with Sézary syndrome.1, 6 No complete responses, defined as 100% clearing of all findings, were observed.1, 6 Overall response rates for regimens 1, 2, and 3 were about 31, 9, and 33%, respectively.1, 6 The median time to response in the 8 patients who responded to vorinostat was about 84 days (range: 25-153 days);1, 6 median response duration and median time to progression were 106 (range: 66-136) and about 212 (range: 94-255) days, respectively.1, 6 Compared with the 400-mg once-daily regimen, a dosage of 300 mg twice daily was associated with increased toxicity and no additional clinical benefit.1
Dispensing and Administration Precautions
Administer vorinostat orally once daily with food. Vorinostat capsules should be swallowed whole and should not be opened or crushed.1 Avoid exposure to crushed or broken capsules.1 If the powder comes in direct contact with the skin or mucous membranes, the affected area should be washed thoroughly.1
The recommended adult oral dosage of vorinostat for the treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) refractory to 2 prior systemic therapies is 400 mg once daily.1 The optimal duration of treatment has not been clearly established.1 In clinical trials, treatment generally was continued until evidence of disease progression or unacceptable toxicity was observed.1, 5, 6
Dosage Modification for Toxicity
In patients who do not tolerate a dosage of 400 mg once daily (e.g., because of anemia or thrombocytopenia), the manufacturer recommends reducing the dosage to 300 mg once daily.1 If needed, the dosage may be further reduced to 300 mg once daily for 5 consecutive days each week.1
In patients with mild or moderate hepatic impairment (bilirubin concentration 1-3 times the ULN or AST concentration exceeding the ULN), the manufacturer recommends a starting dosage of 300 mg orally once daily with food.1 The appropriate dosage has not been established in patients with severe hepatic impairment (bilirubin concentration exceeding 3 times the ULN).1
The manufacturer does not make any specific dosage recommendations for patients with renal impairment.1 However, vorinostat is not eliminated renally.1
The manufacturer does not make any specific dosage recommendations for geriatric patients.1
None.1
Pulmonary embolism occurred in 5% of patients treated with vorinostat; deep vein thrombosis was also reported.1 Clinicians should be alert to signs and symptoms of such events, especially in patients with a prior history of thromboembolic events.1
Vorinostat can cause thrombocytopenia and anemia.1 Monitor CBC every 2 weeks for the first 2 months of therapy and monthly thereafter.1 Adjust vorinostat dosage or discontinue the drug, as clinically appropriate, if thrombocytopenia or anemia occurs.1
Nausea, vomiting, and diarrhea are common adverse effects of vorinostat; antiemetic and/or antidiarrheal agents may be required.1 To prevent dehydration, fluid and electrolyte replacement should be administered.1 Preexisting nausea, vomiting, and diarrhea should be adequately controlled before initiating therapy.1
Hyperglycemia, including severe hyperglycemia (5%), can occur during treatment with vorinostat.1 Monitor serum glucose concentrations every 2 weeks for the first 2 months of therapy and monthly thereafter.1 Closely monitor glucose in patients with known or possible diabetes; diet and/or antidiabetic therapy should be adjusted, if needed.1
Monitor blood chemistries (including serum electrolyte [i.e., potassium, magnesium, calcium], and creatinine concentrations) every 2 weeks for the first 2 months of therapy and monthly thereafter.1 More frequent monitoring of serum potassium and magnesium is recommended in symptomatic patients (e.g., patients who develop nausea, vomiting, diarrhea, fluid imbalance, or cardiac symptoms).1 Hypokalemia or hypomagnesemia should be corrected before initiation of therapy.1
Interactions with Other Histone Deacetylase Inhibitors
Concomitant use of vorinostat with other histone deacetylase (HDAC) inhibitors (e.g., valproic acid) may result in severe thrombocytopenia and GI bleeding.1 Monitor platelet count every 2 weeks for the first 2 months in patients concomitantly taking vorinostat and another HDAC inhibitor.1
Fetal/Neonatal Morbidity and Mortality
Vorinostat can cause fetal harm in humans based on its mechanism of action and animal findings.1 The drug crossed the placenta, causing adverse developmental outcomes in animals at doses equivalent to approximately half of the normal human exposure.1 Human data are insufficient to quantify the risk of miscarriage and major birth defects.1 Perform pregnancy testing within 7 days prior to initiating treatment in females of reproductive potential.1 Females of reproductive potential should use effective contraceptive methods during vorinostat therapy and for at least 6 months following discontinuance of the drug.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 Males with female partners of reproductive potential should use effective contraception during vorinostat therapy and for at least 3 months following discontinuance of the drug.1
Vorinostat may cause fetal harm if administered to pregnant females.1
There are no data on the presence of vorinostat in human milk, the effects on the breast-fed infant, or the effects on milk production.1 Females should be advised not to breast-feed while receiving the drug and for at least 1 week following discontinuance of the drug.1
Females and Males of Reproductive Potential
Results of animal studies suggest that vorinostat may impair female fertility.1 In fertility studies, dosage-dependent increases in peri-implantation losses occurred in female animals receiving vorinostat at exposure levels equivalent to 0.15 times the human exposure at the recommended dosa increases in fetal death and resorption were observed at exposure levels equivalent to 0.7 times the human exposure at the recommended dosage.1
Male fertility and reproductive performance were not altered by vorinostat in animal studies.1
Females of reproductive potential should use effective contraceptive methods during vorinostat therapy and for at least 6 months following discontinuance of the drug.1
Males with female partners of reproductive potential should use effective contraception during vorinostat therapy and for at least 3 months following discontinuance of the drug.1
Safety and efficacy have not been established in pediatric patients <18 years of age.1
An insufficient number of patients ≥65 years of age were included in clinical studies of vorinostat to determine whether geriatric patents respond differently than younger adults.1 Available data have not identified response differences between geriatric patients and younger adults.1
In a single-dose pharmacokinetic study of vorinostat 400 mg in patients with non-CTCL cancers, the mean AUC increased by 50% in patients with mild (total bilirubin concentration greater than 1-1.5 times the ULN or AST exceeding the ULN) or moderate (total bilirubin 1.5-3 times the ULN) hepatic impairment compared to patients with normal hepatic function.1 Rates of grade 3 or 4 thrombocytopenia were increased in patients with non-CTCL cancers and mild or moderate hepatic impairment receiving vorinostat 300 mg or 200 mg once daily, respectively.1
In a single-dose pharmacokinetic study of vorinostat 400 mg in patients with non-CTCL cancers, the mean AUC increased by 66% in patients with severe hepatic impairment (total bilirubin exceeding 3 times the ULN) compared to patients with normal hepatic function.1 Daily doses of vorinostat exceeding 200 mg per day have not been studied in patients with severe hepatic impairment; insufficient data are available to recommend an appropriate dosage in severe hepatic impairment.1
Vorinostat has not been studied in patients with renal impairment, but renal excretion is not a significant route of elimination for the drug.1
Adverse effects occurring in ≥20% of patients receiving vorinostat include diarrhea, fatigue, nausea, thromboctyopenia, anorexia, and dysgeusia.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Vorinostat is not metabolized by cytochrome P-450 (CYP) isoenzymes.1 Pharmacokinetic interactions are unlikely with drugs that are CYP enzyme inducers or inhibitors.1
Vorinostat does not inhibit CYP isoenzymes in vitro at therapeutic serum concentrations.1 Pharmacokinetic interactions with drugs metabolized by these isoenzymes are unlikely.1
Drugs Affecting Efflux Transport Systems
Vorinostat is not a substrate of P-glycoprotein (P-gp) and does not inhibit P-gp at therapeutic concentrations.1 Pharmacokinetic interactions are unlikely via P-gp transport pathways.1
Prolongation of prothrombin time (PT) or international normalized ratio (INR) is possible in patients receiving vorinostat concomitantly with coumarin-derivative antiacoagulants.1 PT and INR should be monitored more frequently in patients receiving vorinostat with coumarin-derivative anticoagulants.1
Histone Deacetylase Inhibitors
Severe thrombocytopenia and GI bleeding are possible in patients receiving vorinostat concomitantly with other histone deacetylase (HDAC) inhibitors (e.g., valproic acid).1 Platelet count should be monitored every 2 weeks for the first 2 months.1
Vorinostat, a histone deacetylase inhibitor, is an antineoplastic agent.1, 2, 3 The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.1, 3 Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations.1, 3 HDAC enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors.1, 3 Overexpression of HDAC enzymes or aberrant recruitment of HDAC enzymes to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones has been observed in some cancer cells.1, 3 Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription.1, 3 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.1, 3 In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells.1, 2, 3
Vorinostat is extensively metabolized to inactive metabolites, principally by glucuronidation and hydrolysis followed by β-oxidation.1, 4 The drug is not metabolized by cytochrome P-450 (CYP) isoenzymes.1 In vitro studies indicate that vorinostat is not a substrate of human P-glycoprotein and does not inhibit the P-glycoprotein transport system.1 Vorinostat is excreted principally (about 35-52%) in urine as 2 major, inactive metabolites.1, 4 Only a small portion (<1%) of a dose is excreted in urine as unchanged drug.1, 4
Inform clinicians of any history of pulmonary embolism, deep-vein thrombosis, or diabetes mellitus.1
Notify clinician immediately if sudden swelling in leg, leg pain or tenderness, increased warmth in area of swelling, skin redness, skin color change, sudden sharp chest pain, shortness of breath, cough with bloody secretions, sweating, rapid pulse, fainting, or anxiety occurs.1
Advise patients to swallow capsules whole and of not chewing or opening the capsules.1 If capsules are accidentally opened or crushed, importance of not touching capsules or powder contents.1 If powder contacts skin or eyes, importance of washing area well with plain water and informing a clinician.1
Advise patients to take vorinostat with food.1
Advise patients that if a dose of vorinostat is missed, it should be taken as soon as remembered.1 If it is close to the next dose, patients should be advised to take the drug at the regularly scheduled time.1
Advise patients to drink at least 2 L of water every day while taking the drug.1 Importance of informing clinician immediately if excessive vomiting or diarrhea occurs or if unable to eat or drink normally because of nausea, vomiting, or diarrhea.1
Advise patients with high blood sugar (hyperglycemia) or diabetes mellitus to continue monitoring serum glucose concentrations; antidiabetic therapy may require adjustment by a clinician.1
Inform clinician if fatigue, pallor, shortness of breath, or unusual bruising develops.1
Inform patient that regular blood tests will be performed to check blood counts and chemistries during therapy.1
Advise females to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant females of risk to the fetus.1
Instruct patients to inform clinicians of existing or contemplated concomitant therapy, including prescription (e.g., valproic acid, anticoagulants) and OTC drugs and herbal supplements, as well as any concomitant illnesses.1
Inform patients of other important precautionary information.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 28, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Merck Sharp & Dohme, LLC. Zolinza® (vorinostat) capsules prescribing information. Rahway, NJ; 2022 Jul.
2. Duvic M, Zhang C. Clinical and laboratory experience of vorinostat (suberoylanilide hydroxamic acid) in the treatment of cutaneous T-cell lymphoma. Br J Cancer . 2006; 95:S13-9.
3. Richon VM. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer . 2006; 95:S2-6.
4. Rubin EH, Agrawal NGB, Friedman EJ et al. A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res . 2006; 12:7039-45. [PubMed 17145826]
5. Olsen EA, Kim YH, Kuzel TM et al. Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol . 2007; 25: (epub ahead of print). DOI: 10.1200/JCO.2006.10.2434.
6. Duvic M, Talpur R, Ni X et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood . 2007; 109:31-9. [PubMed 16960145]
7. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2022 December 12 [Web]
8. Anon. Vorinostat (Zolinza) for cutaneous T-cell lymphoma. Med Lett . 2007; 49:23-4.