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