rate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].
10 OVERDOSAGE
No specific information is available on the treatment of overdosage of ISTODAX.
Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.
11 DESCRIPTION
Romidepsin, a histone deacetylase (HDAC) inhibitor, is a bicyclic depsipeptide. At room temperature, romidepsin is a white powder and is described chemically as (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone. The empirical formula is C24H36N4O6S2.
The molecular weight is 540.71 and the structural formula is:
ISTODAX (romidepsin) for injection is intended for intravenous infusion only after reconstitution with the supplied Diluent and after further dilution with 0.9% Sodium Chloride, USP.
ISTODAX is supplied as a kit containing two vials.
ISTODAX (romidepsin) for injection is a sterile lyophilized white powder and is supplied in a single-use vial containing 10 mg romidepsin and 20 mg povidone, USP.
Diluent for ISTODAX is a sterile clear solution and is supplied in a single-use vial containing a 2-mL deliverable volume. Diluent for ISTODAX contains 80% (v/v) propylene glycol, USP and 20% (v/v) dehydrated alcohol, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.
12.3 Pharmacokinetics
Absorption
Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m2 when administered intravenously over 4 hours in patients with advanced cancers.
In patients with T cell lymphomas who received 14 mg/m2 of romidepsin intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-inf) were 377 ng/mL and 1549 ng*hr/mL, respectively.
Distribution
Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration rang |
