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Vorinostat

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: N-hydroxy-N'-phenyloctanediamide
Molecular Formula: C14H20N2O3
CAS Number: 149647-78-9
Brands: Zolinza

Introduction

Vorinostat, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1 2 3

Uses for Vorinostat

Cutaneous T-cell Lymphoma

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

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Designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.7

Vorinostat Dosage and Administration

General

Avoid exposure to crushed or broken capsules.1 If the powder comes in direct contact with the skin or mucous membranes, wash affected area thoroughly.1

May continue treatment until evidence of disease progression or unacceptable toxicity observed.1 5 6

Administration

Oral Administration

Administer orally with food.1 Swallow capsules whole; do not open or crush.1

Dosage

Adults

Cutaneous T-cell Lymphoma
Oral

400 mg once daily.1

In patients who do not tolerate a dosage of 400 mg once daily (e.g., because of anemia or thrombocytopenia), reduce dosage to 300 mg once daily.1 If needed, may further reduce dosage to 300 mg once daily for 5 consecutive days each week.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Vorinostat

Contraindications

  • Manufacturer states that there are no known contraindications to use of vorinostat.1

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;1 teratogenicity demonstrated in animals.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Major Toxicities

Thromboembolism

Risk of pulmonary embolism and DVT.1 Clinicians should be alert to signs and symptoms of such effects, especially in patients with prior history of thromboembolic events.1

Hematologic Effects

Risk of dose-related thrombocytopenia and anemia.1 Adjust dosage or discontinue therapy if thrombocytopenia or anemia occurs.1 (See Dosage under Dosage and Administration.)

GI Effects

Risk of nausea, vomiting, and diarrhea;1 may require antiemetic and/or antidiarrheal agents.1

Administer fluid and electrolyte replacement to prevent dehydration.1 Adequately control preexisting nausea, vomiting, and diarrhea before initiating therapy.1

Hyperglycemia

Risk of hyperglycemia.1 Monitor serum glucose concentrations, especially in patients with known or possible diabetes mellitus.1 Adjust diet and/or antidiabetic therapy, if needed.1

General Precautions

Adequate Patient Monitoring

Carefully monitor CBCs and blood chemistries (including serum electrolyte [i.e., potassium, magnesium, calcium], glucose, and creatinine concentrations) every 2 weeks for the first 2 months of therapy and monthly thereafter.11 Correct hypokalemia or hypomagnesemia before initiation of therapy.11 Consider monitoring of serum potassium and magnesium in symptomatic patients (e.g., patients who develop nausea, vomiting, diarrhea, fluid imbalance, or cardiac symptoms).11

Interactions with other Histone Deacetylase (HDAC) Inhibitors

Concomitant use with other HDAC inhibitors (e.g., valproic acid) may result in severe thrombocytopenia and GI bleeding.1 Monitor platelet count every 2 weeks during the first 2 months.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether vorinostat is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1 Since drug is extensively metabolized, use with caution in patients with hepatic impairment.1

Renal Impairment

Not studied in patients with renal impairment.1 Although drug is not renally excreted, the manufacturer states to use with caution in patients with preexisting renal impairment.1

Common Adverse Effects

Diarrhea,1 2 5 6 fatigue,1 2 5 6 nausea,1 2 5 6 dysgeusia,1 2 5 6 thrombocytopenia,1 2 5 6 anorexia,1 5 weight loss,1 5 muscle spasms,1 5 alopecia,1 5 dry mouth,1 5 6 increased Scr,1 5 chills,1 5 vomiting,1 5 constipation,1 5 dizziness,1 anemia,1 5 6 decreased appetite,1 peripheral edema,1 headache,1 pruritus,1 cough,1 upper respiratory infection,1 pyrexia.1 6

Interactions for Vorinostat

Not metabolized by CYP isoenzymes.1 Pharmacokinetic interactions unlikely with drugs that are CYP enzyme inducers or inhibitors.1

Does not inhibit CYP isoenzymes in vitro at therapeutic serum concentrations.1 Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.1

Specific Drugs

Drug

Interaction

Comments

Coumarin-derivative anticoagulants

Possible prolongation of PT and INR1

Carefully monitor PT and INR1

HDAC inhibitors (e.g., valproic acid)

Possibility of severe thrombocytopenia and GI bleeding1

Monitor platelet count every 2 weeks for the first 2 months1

Vorinostat Pharmacokinetics

Absorption

Bioavailability

Following administration of a single 400-mg oral dose to adult cancer patients in the fasted state, median time to peak plasma concentrations was about 1.5 hours (0.5–10 hours).1 4

Food

Administration with a high-fat meal increases extent and decreases rate of absorption; median time to peak plasma concentrations was 4 hours (range: 2–10 hours).1 4

Distribution

Plasma Protein Binding

About 71% (mainly to plasma proteins).1

Elimination

Metabolism

Extensively metabolized to inactive metabolites, principally by glucuronidation and hydrolysis followed by β-oxidation.1 4 Not metabolized by CYP isoenzymes.1

Elimination Route

Excreted principally (about 35–52%) in urine as the 2 major, inactive metabolites.1 4

Only a small portion (<1%) of a dose is excreted in urine as unchanged drug.1 4

Half-life

About 2 hours.1 4

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Histone deacetylase inhibitor; antineoplastic agent.1 2 3

  • Inhibits 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 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 accumulation of acetyl groups on the histone lysine residues, resulting in an open chromatin structure and transcriptional activation.1 3

  • In vitro, causes accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells.1 3

Advice to Patients

  • Importance of informing clinician of history of pulmonary embolism, DVT, or diabetes mellitus.11

  • Risk of DVT and pulmonary embolism.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

  • Importance of swallowing capsules whole; do not chew or break open.1 If capsules are accidentally opened or crushed, importance of not touching capsules or powder contents.1 If powder contacts skin or eyes, wash area well with plain water and inform clinician.1

  • Importance of taking vorinostat with food.1

  • Importance of advising patient that if a dose of vorinostat is missed; it should be taken as soon as remembered.1 If it is close to next dose, take it at the regularly scheduled time.1

  • Importance of contacting clinician, local emergency room, or poison control center immediately in case of overdosage.1

  • Importance of drinking at least 2 L of liquids every day while taking the drug.1 Risk of nausea, vomiting, and diarrhea; dehydration may occur.1 Inform clinician immediately if excessive vomiting or diarrhea occurs or if unable to eat or drink normally because of nausea, vomiting, or diarrhea.1

  • Patients with high blood sugar (hyperglycemia) or diabetes mellitus should continue monitoring serum glucose concentrations; diabetes mellitus therapy may require adjustment by clinician.11

  • Importance of informing clinician if fatigue, pallor, shortness of breath or unusual bruising develops.1

  • Importance of informing patient that regular blood tests will be performed to check blood counts and chemistries during therapy.11

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1 Particularly important to inform clinician if taking valproic acid or anticoagulants.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Vorinostat

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg

Zolinza

Merck

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck & Co., Inc. Zolinza (vorinostat) capsules prescribing information. Whitehouse Station, NJ; 2006 Oct.

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. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [Jun 1, 2007]. From FDA web site .

8. Anon. Vorinostat (Zolinza) for cutaneous T-cell lymphoma. Med Lett Drugs Ther. 2007; 49:23-4.

9. Merck & Co., Inc. North Wales, PA: Personal communication.

10. Merck & Co., Inc. Patient information: Zolinza (vorinostat) capsules patient information. Whitehouse Station, NJ; 2006 Oct.

11. Merck & Co., Inc. Zolinza (vorinostat) capsules prescribing information. Whitehouse Station, NJ; 2010 Feb..

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