Vorinostat

Pronunciation: vor-IN-oh-stat
Class: Histone deacetylase inhibitor

Trade Names

Zolinza
- Capsules, oral 100 mg

Pharmacology

Inhibits enzymatic activity of histone deacetylases (HDACs) at nanomolar concentrations. These enzymes catalyze the removal of acetyl groups from the lysine residue of proteins, including histones and transcription factors.

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Pharmacokinetics

Absorption

When administered with high-fat meal, C _max is 1.2 mcM and T _max is 4 h. The extent of absorption is increased 33% when taken with a high-fat meal.

Distribution

Plasma protein binding is approximately 71%.

Metabolism

Metabolism involves glucuronidation and hydrolysis followed by beta-oxidation.

Elimination

Less than 1% of an administered dose is recovered unchanged in the urine. Total urinary recovery of vorinostat and 2 inactive metabolites averages 52%. Mean terminal half-life is 2 h.

Special Populations

Not evaluated; renal excretion does not play a role in the elimination of vorinostat.

An ongoing pharmacokinetic study showed higher incidence and severity of adverse reactions in patients with severe hepatic dysfunction.

Age does not appear to have a meaningful effect on vorinostat pharmacokinetics.

Not evaluated in patients younger than 18 y.

Gender does not appear to have a meaningful effect on vorinostat pharmacokinetics.

Race does not appear to have a meaningful effect on vorinostat pharmacokinetics.

Indications and Usage

Treatment of cutaneous manifestation in patients with cutaneous T-cell lymphoma who have progressive, persistent, or recurrent disease during or following 2 systemic therapies.

Contraindications

Severe hepatic impairment.

Dosage and Administration

PO 400 mg once daily with food, continued as long as there is no evidence of progressive disease or unacceptable toxicity. If a patient is intolerant to therapy, the dosage may be reduced to 300 mg once daily with food; the dosage may be further reduced to 300 mg once daily with food for 5 consecutive days each week, as necessary.

General Advice

• Should be taken with food and at least 8 oz of liquid.
• Capsules should not be opened or crushed.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Prolongation of PT and INR may be prolonged.

The risk of GI bleeding and severe thrombocytopenia may be increased. Monitor platelet count every 2 wk for the first 2 mo.

Adverse Reactions

CNS

Fatigue (52%); dizziness (15%); headache (12%); pyrexia (11%).

Dermatologic

Alopecia (19%); pruritus (12%).

GI

Diarrhea (52%); nausea (41%); dysgeusia (28%); anorexia (24%); dry mouth (16%); constipation, vomiting (15%); decreased appetite (14%).

Hematologic-Lymphatic

Thrombocytopenia (26%); anemia (14%).

Lab Tests

Increased serum glucose (69%); proteinuria (51%); increased serum creatinine (46%); increased blood creatinine (16%).

Metabolic-Nutritional

Decreased weight (21%).

Musculoskeletal

Muscle spasms (20%).

Respiratory

Cough, upper respiratory tract infection (11%); pulmonary embolism (5%).

Miscellaneous

Chills (16%); peripheral edema (13%); squamous cell carcinoma (4%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Not evaluated; use with caution.

Hepatic Function

Contraindicated in patients with severe hepatic impairment; use with caution in patients with mild or moderate hepatic impairment.

GI

GI disturbances, including diarrhea, nausea, and vomiting, may occur. Antiemetic and antidiarrheal medications may be needed.

Hematologic

Dose-related thrombocytopenia and anemia may occur.

Hyperglycemia

May occur. Monitor serum glucose.

QTc prolongation

Although not studied, QTc prolongation has been reported.

Thromboembolism

Pulmonary embolism and deep vein thrombosis may occur.

Overdosage

Symptoms

No information is available.

Patient Information

• Advise patients to read the patient information leaflet before using vorinostat the first time and with each refill.
• Instruct patients to take vorinostat exactly as prescribed and not to change the dose or discontinue therapy unless advised by their health care provider.
• Instruct patients to take the medicine with food and to drink at least 8 oz of liquid when taking the capsule.
• Instruct patients to drink at least 2 L/day of fluid to prevent dehydration.
• Advise patients to swallow capsule whole and not to open or crush capsule.
• Instruct patients to report excessive diarrhea or vomiting to their health care provider.
• Instruct patients to seek immediate medical attention if unusual bleeding occurs.
• Advise patients that if a dose is missed to take it as soon as they remember. If it is almost time for the next dose, tell them to skip the missed dose and go back to the regular dosing schedule. Advise patients not to take 2 doses at the same time.
• Advise patients to keep all appointments and that blood cell counts, blood sugar, and other chemistries will be monitored every 2 wk for the first 2 mo of treatment then every month thereafter.

Copyright © 2009 Wolters Kluwer Health.