Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Zolinza: 100 mg
Pharmacology
Mechanism of Action
Vorinostat inhibits histone deacetylase enzymes, HDAC1, HDAC2, HDAC3, and HDAC6, which catalyze acetyl group removal from protein lysine residues (including histones and transcription factors). Histone deacetylase inhibition results in accumulation of acetyl groups, which alters chromatin structure and transcription factor activation; cell growth is terminated and apoptosis occurs.
Pharmacokinetics/Pharmacodynamics
Metabolism
Glucuronidated and hydrolyzed (followed by beta-oxidation) to inactive metabolites
Excretion
Urine: ~52% (~52% as inactive metabolites; <1% as unchanged drug)
Time to Peak
Plasma: With high-fat meal: 4 hours (range: 2 to 10 hours)
Half-Life Elimination
~2 hours
Protein Binding
~71%
Use in Specific Populations
Special Populations: Hepatic Function Impairment
In a single 400 mg dose pharmacokinetic study in cancers other than cutaneous T-cell lymphoma, the AUC was increased by 50% in patients with mild (bilirubin >1 to 1.5 times ULN or AST > ULN with bilirubin ≤ ULN) and moderate (bilirubin 1.5 to ≤3 times ULN) impairment, and increased by 66% in patients with severe impairment (bilirubin >3 times ULN), compared to patients with normal hepatic function.
Use: Labeled Indications
Cutaneous T-cell lymphoma: Treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic treatments.
Contraindications
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to vorinostat or any component of the formulation; severe hepatic impairment (total bilirubin ≥3 times ULN)
Dosage and Administration
Dosing: Adult
Cutaneous T-cell lymphoma (CTCL): Oral: 400 mg once daily until disease progression or unacceptable toxicity (Duvic 2007; Olsen 2007).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Intolerance: Reduce dose to 300 mg once daily; if needed, may further reduce to 300 mg daily for 5 consecutive days per week.
In clinical trials, treatment was withheld for grade 4 anemia or thrombocytopenia or other grade 3 or 4 drug-related toxicity, until resolved to ≤ grade 1 and then was reinitiated with dose reduction (Duvic 2007; Olsen 2007). Vorinostat was discontinued in patients requiring more than 2 dose modifications or if a toxicity did not resolve within 2 weeks (Duvic 2007).
Extemporaneously Prepared
Although not recommended by the manufacturer, a 50 mg/mL oral suspension may be prepared with capsules. Add 20 mL Ora-Plus® into a glass bottle (≥4 oz). Add the contents of twenty 100 mg capsules and shake thoroughly to disperse (may take up to 3 minutes). Add 20 mL Ora-Sweet® and shake to disperse. Label “shake well”. Stable for 14 days at room temperature.
Fouladi M, Park JR, Stewart CF, et al, "Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report," J Clin Oncol, 2010, 28(22):3623-9.20606092
Administration
Oral: Administer with food. Do not open, crush, break, or chew capsules. Maintain adequate hydration (≥2 L/day fluids) during treatment.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Drug Interactions
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Valproate Products: May enhance the thrombocytopenic effect of Vorinostat. This may increase the risk of gastrointestinal bleeding. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Vorinostat may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Adverse Reactions
>10%:
Cardiovascular: Peripheral edema (13%)
Central nervous system: Fatigue (52%), chills (16%), dizziness (15%), headache (12%)
Dermatologic: Alopecia (19%), pruritus (12%)
Endocrine & metabolic: Hyperglycemia (8% to 69%; grade 3: 5%), weight loss (21%), dehydration (1% to 16%)
Gastrointestinal: Diarrhea (52%), nausea (41%), dysgeusia (28%), anorexia (24%), xerostomia (16%), constipation (15%), vomiting (15%), decreased appetite (14%)
Genitourinary: Proteinuria (51%)
Hematologic & oncologic: Thrombocytopenia (26%; grades 3/4: 6%), anemia (14%; grades 3/4: 2%)
Neuromuscular & skeletal: Muscle spasm (20%)
Renal: Increased serum creatinine (16% to 47%)
Respiratory: Cough (11%), upper respiratory tract infection (11%)
Miscellaneous: Fever (11%)
1% to 10%:
Cardiovascular: Pulmonary embolism (5%), prolonged Q-T interval on ECG (3% to 4%)
Hematologic & oncologic: Squamous cell carcinoma of skin (4%)
<1%, postmarketing, and/or case reports: Abdominal pain, acute ischemic stroke, angioedema, bacteremia (streptococcal), blurred vision, chest pain, cholecystitis, deafness, deep vein thrombosis, diverticulitis, dysphagia, exfoliative dermatitis, gastrointestinal hemorrhage, Guillain-Barre syndrome, hemoptysis, hypertension, hypokalemia, hyponatremia, infection, infection due to enterococcus, lethargy, leukopenia, myocardial infarction, neutropenia, pneumonia, renal failure, sepsis, spinal cord injury, syncope, T-cell lymphoma, tumor hemorrhage, ureteral obstruction, obstructive uropathy (ureteropelvic junction), urinary retention, vasculitis, weakness
Warnings/Precautions
Concerns related to adverse effects:
- Bone marrow suppression: Dose-related anemia and thrombocytopenia may occur; may require dosage reduction or discontinuation. Monitor blood counts (every 2 weeks for 2 months, then monthly). Gastrointestinal bleeding due to severe thrombocytopenia has been reported in patients receiving vorinostat in combination with other histone deacetylase inhibitors (eg, valproic acid); monitor platelet counts more frequently in patients receiving concomitant histone deacetylase inhibitor therapy.
- CNS effects: May cause dizziness or fatigue; caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).
- Gastrointestinal toxicities: Nausea, vomiting, and diarrhea may occur; antiemetics and antidiarrheals may be required. Replace fluids and electrolytes to avoid dehydration. Control preexisting nausea, vomiting, and diarrhea prior to treatment initiation. Adverse anastomotic healing events have occurred in patients recovering from bowel surgery; use with caution in the perioperative period in patients requiring bowel surgery.
- Hyperglycemia: May cause hyperglycemia (may be severe). Monitor serum glucose every 2 weeks for 2 months, then monthly, or as clinically necessary. Use with caution in patients with diabetes; may require diet and/or antidiabetic therapy modifications.
- QTc prolongation: QTc prolongation has been observed. Correct electrolyte abnormalities prior to treatment and monitor and correct potassium, calcium, and magnesium levels during therapy. Use caution in patients with a history of QTc prolongation or with medications known to prolong the QT interval. Baseline and periodic ECGs were done in clinical trials (Duvic 2007; Olsen 2007).
- Thromboembolic events: Pulmonary embolism and deep vein thrombosis (DVT) have been reported; monitor for signs/symptoms, especially in patients with a history of thrombotic events.
Disease-related issues:
- Hepatic impairment: Use with caution in patients with hepatic impairment; dose reductions are recommended (elimination is predominantly hepatic).
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Monitoring Parameters
CBC with differential and serum chemistries, including calcium, magnesium, potassium, glucose and creatinine (baseline, then every 2 weeks for 2 months, then monthly, or as clinically necessary), hepatic function, INR (if on concomitant warfarin therapy). Monitor fluid status and for signs/symptoms of thromboembolism. Monitor adherence.
Baseline and periodic ECGs were done in clinical trials (Duvic 2007; Olsen 2007).
Pregnancy
Pregnancy Considerations
Based on the mechanism of action and data from animal reproduction studies, vorinostat may cause fetal harm if administered during pregnancy. Inform patient of potential hazard if used during pregnancy or if pregnancy occurs during treatment.
Evaluate pregnancy status prior to treatment. Pregnancy testing should be conducted within 7 days prior to treatment in females of reproductive potential. Females of reproductive potential should avoid pregnancy and use an effective contraceptive during therapy and for at least 6 months after the last vorinostat dose. Males with female partners of reproductive potential should use effective contraception during therapy and for at least 3 months after the last vorinostat dose.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, chills, cough, muscle spasms, lack of appetite, weight loss, constipation, change in taste, hair loss, itching, or signs of common cold. Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of dehydration (dry skin, dry mouth, dry eyes, increased thirst, fast heartbeat, dizziness, fast breathing, or confusion), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), fast heartbeat, passing out, swelling of arms or legs, sweating a lot, anxiety, severe nausea, severe vomiting, severe diarrhea, severe loss of strength and energy, pale skin, diarrhea, or fatigue (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
