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Vorinostat

Pronunciation

(vor IN oh stat)

Index Terms

  • SAHA
  • Suberoylanilide Hydroxamic Acid

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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Capsule, Oral:

Zolinza: 100 mg

Brand Names: U.S.

  • Zolinza

Pharmacologic Category

  • Antineoplastic Agent, Histone Deacetylase (HDAC) Inhibitor

Pharmacology

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.

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%

Special Populations: Hepatic Function Impairment

In a pharmacokinetic study in cancers other than cutaneous T-cell lymphoma, the AUC was increased 50% in patients with mild and moderate impairment, and increased 66% in patients with severe impairment, compared to patients with normal hepatic function.

Use: Labeled Indications

Cutaneous T-cell lymphoma: Treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) with progressive, persistent, or recurrent disease on or following 2 systemic treatments

Contraindications

There are no contraindications in the manufacturer’s U.S. labeling.

Canadian labeling: Hypersensitivity to vorinostat or any component of the formulation; severe hepatic impairment (total bilirubin ≥3 times ULN)

Dosage

Cutaneous T-cell lymphoma (CTCL): Adults: Oral: 400 mg once daily until disease progression or unacceptable toxicity

Dosage adjustment for toxicity:

U.S. labeling: Intolerance: Reduce dose to 300 mg once daily; if needed, may further reduce to 300 mg daily for 5 consecutive days per week

Canadian labeling: Grade 3 or 4 toxicity: Interrupt therapy until resolves to ≤grade 1 (excluding grade 3 anemia and thrombocytopenia). Upon recovery, may reduce dose to 300 mg once daily. If necessary, may further reduce dose to 300 mg once daily for 5 consecutive days per week.

Additionally, in clinical trials, dose reductions were instituted for the following adverse events: Increased serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia, and vomiting. Vorinostat was discontinued for the following adverse events: Anemia, angioneurotic edema, weakness, chest pain, exfoliative dermatitis, DVT, ischemic stroke, lethargy, pulmonary embolism, and spinal cord injury.

Treatment was withheld in clinical trials for grade 4 anemia or thrombocytopenia or other grade 3 or 4 drug related toxicity, until resolved to ≤grade 1. Treatment was reinitiated with dose reduction (Olsen, 2007).

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, based on the minimal renal elimination, adjustment not expected. Use with caution.

Dosage adjustment in hepatic impairment:

U.S. labeling: Initial:

Mild-to-moderate impairment (total bilirubin 1 to 3 times ULN or AST >ULN): 300 mg once daily

Severe impairment (total bilirubin >3 times ULN): There are no dosage adjustments provided in manufacturer’s labeling (evidence is insufficient for a starting dose recommendation). Doses of 100 to 200 mg once daily were studied in a limited number of patients with severe impairment (Ramalingam, 2010); according to the manufacturer, the maximum dose used was 200 mg once daily.

Canadian labeling:

Mild impairment (total bilirubin >1 to 1.5 times ULN or total bilirubin ≤ULN and AST >ULN): 300 mg once daily

Moderate impairment (total bilirubin 1.5 to 3 times ULN): Use is not recommended

Severe impairment (total bilirubin ≥3 times ULN): Use is contraindicated

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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

Administer with food. Do not open, crush, break, or chew capsules. Maintain adequate hydration (≥2 L/day fluids) during treatment.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Avoid direct skin or mucous membrane contact with crushed or broken capsules and/or capsule contents.

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

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. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Mifepristone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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%), fever (11%)

Dermatologic: Alopecia (19%), pruritus (12%)

Endocrine & metabolic: Hyperglycemia (8% to 69%; grade 3: 5%), dehydration (1% to 16%)

Gastrointestinal: Diarrhea (52%), nausea (41%), taste alteration (28%), anorexia (24%), weight loss (21%), xerostomia (16%), constipation (15%), vomiting (15%), appetite decreased (14%)

Hematologic: Thrombocytopenia (26%; grades 3/4: 6%), anemia (14%; grades 3/4: 2%)

Neuromuscular & skeletal: Muscle spasm (20%)

Renal: Proteinuria (51%), creatinine increased (16% to 47%)

Respiratory: Cough (11%), upper respiratory infection (11%)

1% to 10%:

Cardiovascular: QTc prolongation (3% to 4%)

Dermatologic: Squamous cell carcinoma (4%)

Respiratory: Pulmonary embolism (5%)

<1% (Limited to important or life-threatening): Abdominal pain, angioneurotic edema, blurred vision, chest pain, cholecystitis, deafness, diverticulitis, dysphagia, DVT, enterococcal infection, exfoliative dermatitis, gastrointestinal bleeding, gastrointestinal hemorrhage, Guillain-Barré syndrome, hemoptysis, hypertension, hypokalemia, hyponatremia, infection, lethargy, leukopenia, MI, neutropenia, pneumonia, renal failure, sepsis, spinal cord injury, streptococcal bacteremia, stroke (ischemic), syncope, T-cell lymphoma, tumor hemorrhage, ureteric obstruction, ureteropelvic junction obstruction, 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). Use with caution in patients with diabetes mellitus; monitor serum glucose every 2 weeks for 2 months, then monthly, or as clinically necessary; may require diet and/or 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. Use with caution 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). The Canadian labeling does not recommend use in patients with moderate hepatic impairment (total bilirubin 1.5 to 3 times ULN) and contraindicates use in severe hepatic impairment (bilirubin ≥3 times ULN).

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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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), fluid status, signs/symptoms of thromboembolism. Baseline and periodic ECGs were done in clinical trials (and are recommended in the Canadian labeling).

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, may cause fetal harm if administered during pregnancy. Inform patient of potential hazard if used during pregnancy or if pregnancy occurs during treatment.

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, muscle spasms, lack of appetite, constipation, parageusia, alopecia, or xerostomia. Have patient report immediately to prescriber signs of hyperglycemia, dyspnea, angina, tachycardia, severe dizziness, syncope, edema of extremities, painful extremities, considerable nausea, significant diarrhea, excessive weight loss, melena, ecchymosis, hemorrhaging, or intolerable asthenia (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 healthcare 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.

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