vorinostat (Rx)

>10%

Diarrhea (52%)

Fatigue (52%)

Nausea (41%)

Dysguesia (28%)

Thrombocytopenia (26%)

Anorexia (24%)

Weight loss (20.9%)

Muscle spasms (19.8%)

Alopecia (18.6%)

Chills (16%)

Dry mouth (16%)

Increase serum Cr (16%)

Dizziness (15%)

Constipation (15%)

Vomiting (15%)

Anemia (14%)

Peripheral edema (12.8%)

Headache (11.6%)

Pruritus (11.6%)

Cough (10.5%)

Upper respiratory infection (10.5%)

Decreased appetite

Pyrexia

1-10%

Prolonged QT interval (3.5-6%)

Pulmonary embolism (4.7%)

Contraindications

Severe hepatic Impairment

Cautions

Congenital long QT syndrome, drugs/conditions that prolong QT interval; correct hypokalemia or hypomagnesemia before commencing treatment

Thrombocytopenia and anemia may require dose modification or discontinuation; monitor blood counts every 2 weeks during first 2 months of therapy and monthly thereafter

Severe thrombocytopenia with gastrointestinal bleeding reported with other HDAC inhibitors (e.g., valproic acid); monitor platelet counts more frequently

Monitor for pertinent signs and symptoms of pulmonary embolism and deep vein thrombosis

Potential for hyperglycemia; caution in diabetes; monitor blood glucose every 2 weeks during first 2 months of therapy and monthly thereafter

Dose related anemia and thrombocytopenia may occur; modify dose or discontinue if reduction in platelets or Hgb

Concomitant valproic acid

May cause dizziness or fatigue

Concomitant coumarin-derived anticoagulants

Hepatic/renal impairment

Nausea, vomiting and diarrhea; patients may require antiemetics, antidiarrheals, and fluid and electrolyte replacement to prevent dehydration

Avoid pregnancy

Drink at least 2 L of fluids daily

Measure and correct abnormal electrolytes, creatinine, magnesium and calcium at baseline; monitor every 2 weeks during first 2 months of therapy and at least monthly during treatment

Pregnancy

Based on mechanism of action and findings from animal studies, therapy can cause fetal harm when administered to a pregnant woman

There are insufficient data in pregnant women to inform a drug-associated risk of major birth defects and miscarriage

Advise pregnant women of potential risk to fetus

Animal data

• In animal reproduction studies, administration of drug to pregnant rats and rabbits during period of organogenesis caused adverse developmental outcomes at maternal exposures approximately 0.5 times the human exposure based on AUC0-24 hours

Reproductive potential

• Can cause fetal harm when administered to a pregnant woman

Pregnancy testing

• Perform pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy

Contraception

• Females: Advise patients of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose
• Males: Advise males with female partners of reproductive potential to use effective contraception and to avoid fathering a child during treatment with ZOLINZA and for at least 3 months after the last dose

Infertility

• Based on findings in animals, therapy has the potential to affect female fertility

Lactation

There are no data on presence of drug or its metabolites in human milk, effects on a breastfed child, or on milk production; because many drugs are excreted in human milk and because of potential for serious adverse drug reactions in a nursing child, advise lactating women not to breastfeed during treatment and for at least 1 week after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Histone deacetylase inhibitor for enzymes HDAC1, HDAC2, HDAC3, and HDAC6, which in turn alters chromatin structure and transcription factor activation; as a result, cell growth is terminated and apoptosis occurs

Absorption

Peak plasma time: 4 hr

Peak plasma concentration (400 mg dose): 1.2±0.62 umol/L

Fasted state has quicker peak time, but lower AUC and peak concentration

Taken with a high fat meal increases extent of absorption by 33%

Bioavailability: 43%

Distribution

Protein Bound: 71%

Metabolism

Liver

Metabolites: Inactive

Elimination

Half-Life, Terminal: 2 hr

Excretion: Urine 52%

Oral Administration

Take with food

Drink at least 2 L of fluids daily