Panobinostat

Indications

Panobinostat is used for: Indicated for the treatment of patients with, multiple myeloma, who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.

Adult Dose

Multiple Myeloma Indicated in combination with bortezomib and dexamethasone for multiple myeloma in patients who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent 20 mg PO once every other day for 3 doses/week (on Days 1, 3, 5, 8, 10, and 12) of Weeks 1 and 2 of each 21-day cycle for 8 cycles Consider continuing treatment for an additional 8 cycles for patients with clinical benefit, unless they have unresolved severe or medically significant toxicity; the total duration of treatment may be up to 16 cycles (48 weeks) Hepatic impairment Mild: Reduce starting dose to 15 mg Moderate: Reduce starting dose to 10 mg Severe: Avoid use

Child Dose

Renal Dose

Renal impairment Mild-to-severe: Does not impact plasma exposure of panobinostat End-stage renal disease or patients on dialysis: Not studied Dialyzability: Unknown

Administration

Take orally once on each scheduled day at about the same time, either with or without food Swallow capsules whole with a whole cup of water; do not open, crush, or chew the capsules

Contra Indications

Precautions

Hemorrhage: Fatal and serious cases of gastrointestinal and pulmonary hemorrhage. Monitor platelet counts and transfuse as needed. Hepatotoxicity: Monitor hepatic enzymes and adjust dosage if abnormal liver function tests are observed during therapy. Embryo-Fetal Toxicity: can cause fetal harm. Advise women of the potential hazard to the fetus and to avoid pregnancy Severe diarrhea Severe diarrhea reported in 25% of patients Monitor for symptoms; institute antidiarrheal treatment Interrupt panobinostat dosing, and then reduce dose or discontinue Severe cardiac toxicities Severe and fatal cardiac ischemic events reported, including severe arrhythmias and ECG changes Arrhythmias may be exacerbated by electrolyte abnormalities Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated

Pregnancy-Lactation

Pregnancy Perform pregnancy test in women of childbearing potential before initiating treatment Advise females of reproductive potential to avoid becoming pregnant while taking panobinostat Panobinostat was teratogenic in rats and rabbits Advise sexually active females of reproductive potential to use effective contraception while taking panobinostat and for at least 3 months after last dose Advise sexually active men to use condoms while on treatment and for 6 months after last dose Lactation Unknown if distributed in human breast milk

Interactions

Anti-arrhythmic drugs/QT-prolonging drugs: Avoid concomitant use.

Adverse Effects

Side effects of Panobinostat : >10% Percentage refers to all grades unless otherwise noted Thrombocytopenia (97%) Lymphopenia (82%) Leukopenia (81%) Neutropenia (75%) Diarrhea (68%) Hypocalcemia (67%) Thrombocytopenia, grades 3 and 4 (67%) Hypophosphatemia (63%) Hypoalbuminemia (63%) Anemia (62%) Fatigue (60%) Lymphopenia, grades 3 and 4 (53%) Hypokalemia (52%) Hyponatremia (49%) Blood creatinine increased (41%) Nausea (36%) Neutropenia, grades 3 and 4 (34%) Peripheral edema (29%) Hyperphosphatemia (29%) Decreased appetite (28%) Hypermagnesemia (27%) Pyrexia (26%) Vomiting (26%) Diarrhea, grade 3 or 4 (25%) Fatigue, grade 3 or 4 (25%) Leukopenia, grades 3 and 4 (23%) Hyperbilirubinemia (21%) Hypophosphatemia, grades 3 and 4 (20%) Anemia, grades 3 and 4 (18%) Hypokalemia, grades 3 and 4 (18%) Hyponatremia (13%) Weight decreased (12%) Arrhythmias (12%) 1-10% Percentage refers to grades 3 and 4 toxicities Vomiting (7%) Nausea (6%) Hypocalcemia (5%) Hypermagnesemia (5%) Arrhythmias (3%) Decreased appetite (3%) Peripheral edema (2%) Weight decreased (2%) Hypoalbuminemia (2%) Hyperphosphatemia (2%) Pyrexia (1%) Blood creatinine increased (1%) Hyperbilirubinemia (1%)

Mechanism of Action

Histone deacetylase (HDAc) inhibitor; inhibits the enzymatic activity of HDAc at nanomolar concentrations HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells Shows more cytotoxicity towards tumor cells compared with normal cells