ears of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals should be considered, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Use in Patients with Hepatic Impairment
ZOLINZA was studied in 42 patients with non-CTCL cancer and varying degrees of hepatic impairment after single and multiple-dose administration. Compared to patients with normal liver function, AUC increases of 50 to 66% were observed in patients with hepatic impairment. The incidence of Grade 3 or 4 thrombocytopenia increased in patients with mild (bilirubin of 1 to 1.5 × ULN and AST < ULN, or bilirubin ≤ ULN and AST > ULN) and moderate (bilirubin 1.5 to ≤ 3 × ULN) hepatic impairment treated daily at doses of 300 and 200 mg respectively.
Patients with severe hepatic impairment (bilirubin > 3 × ULN) have not been treated at doses greater than 200 mg a day. Reduce the initial dose of ZOLINZA in patients with bilirubin 1 to 3 × ULN or AST > ULN. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3).]
8.7 Use in Patients with Renal Impairment
Vorinostat was not eva luated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. Patients with pre-existing renal impairment should be treated with caution. [See Clinical Pharmacology (12.3).]
10 OVERDOSAGE
No specific information is available on the treatment of overdosage of ZOLINZA.
In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known if vorinostat is dialyzable.
11 DESCRIPTION
ZOLINZA contains vorinostat, which is described chemically as N-hydroxy-N'-phenyloctanediamide.
The empirical formula is C14H20N2O3. The molecular weight is 264.32 and the structural formula is:
Vorinostat is a white to light orange powder. It is very slightly soluble in water, slightly soluble in ethanol, isopropanol and acetone, freely soluble in dimethyl sulfoxide and insoluble in methylene chloride. It has no chiral centers and is non-hygroscopic. The differential scanning calorimetry ranged from 161.7 (endotherm) to 163.9°C. The pH of saturated water solutions of vorinostat drug substance was 6.6. The pKa of vorinostat was determined to be 9.2.
Each 100 mg ZOLINZA capsule for oral administration contains 100 mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate. The capsule shell excipients are titanium dioxide, gelatin and sodium lauryl sulfate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50<86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncog
