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vorinostat
Accumulation of acetylated histones results in transcriptional activation of genes, including tumour suppression genes. HDACs catalyze the removal of the acetyl group from lysine residues of proteins, including histones. Inhibition of HDACs may result in anti-tumour effects. Vorinostat is a histone deacetylase (HDAC) inhibitor, which has effects on HDAC1, HDAC2, HDAC3, and HDAC6. Marketing approval was based on response rates in phase 2 studies.
| Bioavailability | 43% (fasting). A high fat meal increases AUC by 38% and a 2.5 h delay in absorption rate. Peak level is reached in 4 hours. There is no significant accumulation with multiple doses. Pharmacokinetics are linear and dose proportional. |
| Cross blood brain barrier? | yes |
| PPB | 71 % |
Major pathways include glucuronidation or hydrolysis followed by oxidation. Negligible biotransformation by CYP 450 and not a substrate for PGP. Vorinostat has not been shown to inhibit CYP enzymes at pharmacologically relevant concentrations.
| Active metabolites | none |
| Inactive metabolites | o-glucuronide vorinostat, 4-anilino-4-oxobutanoic acid |
Primarily eliminated through metabolism
| Urine |
< 1 % (unchanged) |
| Half-life |
2 hours (vorinostat and o-glucuronide vorinostat) |
Treatment of cutaneous manifestations in patients with advanced cutaneous T-cell lymphoma (CTCL) who have progressive persistent or recurrent disease subsequent to prior systemic therapies
Emetogenic Potential:
Extravasation Potential: Not applicable
The following table contains adverse effects reported mainly as monotherapy in CTCL patients.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial thromboembolism (rare) | E | |||
| Hypertension (rare; reported in non-CTCL patients) | E | ||||
| QT interval prolonged | E | ||||
| Tachycardia | E | ||||
| Venous thromboembolism (7%) | E | ||||
| Dermatological | Alopecia (16%) | E | |||
| Gastrointestinal | Abdominal pain (8%) | E | |||
| Anorexia (23%) | E | ||||
| Constipation (11%) | E | ||||
| Dehydration | E | ||||
| Diarrhea (47%) | E | ||||
| Dry mouth (16%) | E | ||||
| GI hemorrhage (rare, in combination with other HDAC inhibitors) | E | ||||
| GI perforation (or fistula; rare) | E | ||||
| Nausea, vomiting (38%) | E | ||||
| Weight loss (20%) | E | ||||
| General | Delayed wound healing | E | |||
| Fatigue (45%) | E | ||||
| Hematological | Anemia (2%) (severe) | E | |||
| Hemorrhage (tumour; rare; reported in non-CTCL patients) | E | ||||
| Thrombocytopenia (6%) (severe) | E | ||||
| Hypersensitivity | Angioedema (rare) | I | |||
| Hypersensitivity (drug eruption - rare) | E | ||||
| Metabolic / Endocrine | Hyperglycemia (5%) (severe <1%) | E | |||
| ↓ K | E | ||||
| ↓ Na (reported in non-CTCL patients) | E | ||||
| Musculoskeletal | Myalgia (16%) (spasms) | E | |||
| Neoplastic | Secondary malignancy (NSCLC; rare; reported in non-CTCL patients) | D L | |||
| Nervous System | Dizziness (7%) | E | |||
| Dysgeusia (23%) | E | ||||
| Guillain-Barre syndrome (rare; reported in non-CTCL patients) | E | ||||
| Headache (7%) | E | ||||
| Renal | Creatinine increased (13%) | E | |||
| Proteinuria (8%) | E | ||||
| Respiratory | Dyspnea (7%) | E | |||
| Vascular | Vasculitis (rare; reported in non-CTCL patients) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common adverse effects in CTCL patients include fatigue, nausea/vomiting, diarrhea, taste disturbances, dry mouth, anorexia, and thrombocytopenia. Frequencies of adverse effects were higher in non-CTCL patients; however, the types of adverse effects reported were generally similar to those in CTCL patients.
Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, occurs with an increased incidence. Patients with a prior history or at risk of thromboembolic events should be closely monitored. Vorinostat is associated with QT interval prolongation. It should be used with caution in patients with risk factors for QT prolongation or torsade de pointes, such as female gender, age 65 or older, congenital long QT syndrome, cardiac disease, history of arrhythmia, and concomitant medications that prolong QT interval, etc. In the CTCL clinical trial leading to vorinostat approval, there were no grade 3 or higher ECG adverse effects. Increases in heart rate have been described; exercise caution in patients with a history of ischemic heart disease or tachyarrhythmias.
Gastrointestinal effects, such as nausea, vomiting, and diarrhea are usually mild to moderate in severity; some cases may require treatment with antiemetics and antidiarrheals. Women may experience more nausea, diarrhea and dysgeusia than men. Fluid (at least 2 L/day) and/or electrolyte replacement should be administered to prevent dehydration (may be severe) in patients taking vorinostat.
Impaired wound healing has been reported, with fistulas, perforations, and abscess formation.
Dose: 400mg orally once daily with food
Treatment may be continued until disease progression or unacceptable toxicity occurs.
|
Toxicity |
Action |
Dose |
|
Grade 3 |
Hold #* |
↓ 1 dose level |
|
Grade 4 |
Hold #; or discontinue |
If re-start, ↓ 1 dose level |
|
* consider hold for Platelets 10-25 x 109/L and/or Hemoglobin 65-80 g/L if considered related to vorinostat # until recovery to ≤ grade 1 |
||
Although hepatic impairment did not produce statistically significant differences in pharmacokinetics, tolerability decreased with increasing severity of hepatic impairment.
|
Bilirubin
|
AST
|
Action
|
|
|
1 to 1.5 x ULN
|
|
|
Caution; reduce dose to 300 mg daily
|
|
≤ ULN
|
and
|
> ULN
|
Caution; reduce dose to 300 mg daily
|
|
1.5 to ≤ 3 x ULN
|
and
|
any
|
Not recommended for use
|
|
> 3 x ULN
|
and
|
any
|
Contraindicated
|
- Outpatient prescription for home administration.
- Capsules should not be opened or crushed.
- Patients should be instructed to drink at least 2 L/day of fluids for adequate hydration.
Vorinostat is contraindicated in patients who are hypersensitive to the drug or any component in the formulation, and in patients with severe hepatic impairment (total bilirubin > 3 x ULN). Electrolyte abnormalities, pre-existing nausea, vomiting and diarrhea should be controlled prior to vorinostat initiation. Use with caution in diabetics, patients with cardiac risk factors and in patients taking medications which prolong QTc or the PR interval, or mild hepatic impairment (total bilirubin > 1 to 1.5× ULN or total bilirubin ≤ ULN and AST > ULN). Dizziness and syncope have been reported; exercise caution when driving or operating machinery. Exercise caution in patients undergoing bowel surgery or other surgery due to impaired wound healing.
No carcinogenic tests have been conducted. In vitro and animal studies suggest that vorinostat has clastogenic, mutagenic, embryotoxic, fetotoxic effects, and can cross the placenta. It in unknown whether vorinostat is excreted in human milk. Therefore, its use is not recommended in pregnancy and lactation. Adequate contraception should be used by both sexes during vorinostat treatment, and for at least 6 months after treatment cessation.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Warfarin or other coumarin-derivative anticoagulants | Prolonged PT and INR | Unknown | Monitor PT and INR closely |
| HDAC inhibitors (ie: valproic acid) | Grade 4 thrombocytopenia with GI bleeding and anemia | Additive | Avoid concomitant use |
| Drugs that may prolong QT (i.e. Amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of QT interval prolongation | Additive | Avoid concomitant use |
| Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxative, enemas, amphotericin B, high dose corticosteroids) | ↑ risk of QT prolongation | Caution; monitor |
| Monitor Type | Monitor Frequency |
|---|---|
| Liver and renal function tests | Baseline and regular |
| ECG | Baseline and periodic |
| CBC, electrolytes (including Ca, Mg, K) and blood glucose | Baseline, then every 2 weeks during the first 2 months, then monthly thereafter |
| Clinical toxicity assessment of dehydration, hyperglycemia, fatigue, gastrointestinal, and cardiovascular toxicities | Routine |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| Monitor blood glucose closely in diabetic or potentially diabetic patients. |
Galanis E, Jaeckle KA, Maurer MJ, et al. Phase II Trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 2009; 27:2052-2058.
Kelly WK, O’Connor OA, Krug LM, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. JCO 2005; 23: 3923-31.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1287-8.
Product Monograph: Zolinza® (vorinostat). Merck Canada Inc., October 18, 2013.
Yin D, Ong JM, Hu J, et al: Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene expression and growth of glioma cells in vitro and in vivo. Clin Cancer Res 2007; 13:1045-52.
June 2019 Updated emetic risk category.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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