panobinostat (Farydak)

Dosing and uses of Farydak (panobinostat)

• Adult
• Pediatric

 

Adult dosage forms and strengths

capsule

• 10mg
• 15mg
• 20mg

 

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)

Recommended dosing schedule with bortezomib and dexamethasone

• 21-day cycle
• Weeks 1-8
  • Panobinostat on Days 1, 3, 5, 8, 10, and 12, and then rest for 1 week
  • Bortezomib (1.3 mg/m³ IV per scheduled day): Days 1, 4, 8, and 11, and then rest for 1 week
  • Dexamethasone (20 mg PO per scheduled day): Days 1, 2, 4, 5, 8, 9, 11, and 12, and then rest for 1 week
• Weeks 9-16
  • Panobinostat on Days 1, 3, 5, 8, 10, and 12, and then rest for 1 week
  • Bortezomib (1.3 mg/m³ IV per scheduled day): Days 1 and 8, and then rest for 1 week
  • Dexamethasone (20 mg PO per scheduled day): Days 1, 2, 8, and 9, and then rest for 1 week

 

Dosage modifications

Management of adverse drug reactions may require treatment interruption and/or dose reductions

If dose reduction is required, reduce panobinostat dose in increments of 5 mg (ie, from 20 mg to 15 mg, or from 15 mg to 10 mg)

If the dosing is reduced below 10 mg given 3 times per week, discontinue panobinostat

Keep the same treatment schedule (3-week treatment cycle) when reducing dose

Thrombocytopenia

• Platelets <50 x 10^9/L: Maintain panobinostat dose; monitor platelet counts at least weekly
• Platelets <50 x 10^9/L (with grade 3 bleeding): Interrupt panobinostat dosing; monitor platelet counts at least weekly until ≥50 x 10^9/L, then restart at reduced dose
• Platelets <25 x 10^9/L: Interrupt panobinostat dosing; monitor platelet counts at least weekly until ≥50 x 10^9/L, then restart at reduced dose
• Bortezomib dose
  • Platelets <50 x 10^9/L: Maintain dose
  • Platelets <50 x 10^9/L (with grade 3 bleeding) or platelets <25 x 10^9/L: Interrupt bortezomib dosing until thrombocytopenia resolves to ≥75 x 10^9/L
  • If only 1 dose was omitted prior to correction to these levels, restart at same dose; if ≥2 doses were omitted consecutively, or within the same cycle, bortezomib should be restarted at a reduced dose

Neutropenia

• ANC 0.75-1 x 10^9/L: Maintain panobinostat dose
• ANC 0.5-0.75 x 10^9/L (≥2 occurrences): Interrupt panobinostat until ANC ≥1 x 10^9/L, then restart at same dose
• ANC <1 x 10^9/L (with febrile neutropenia): Interrupt panobinostat until ANC ≥1 x 10^9/L, then restart at reduced dose
• ANC <0.5 x 10^9/L: Interrupt panobinostat until ANC ≥1 x 10^9/L, then restart at reduced dose
• Bortezomib dose
  • ANC 0.75-1 x 10^9/L or ANC 0.5-0.75 x 10^9/L (≥2 occurrences): Maintain dose
  • ANC <1 x 10^9/L (with febrile neutropenia) or ANC <0.5 x 10^9/L: Interrupt bortezomib dosing until febrile neutropenia resolves and ANC ≥1 x 10^9/L
  • If only 1 dose was omitted prior to correction to these levels, restart at same dose; if ≥2 doses were omitted consecutively, or within the same cycle, bortezomib should be restarted at a reduced dose

Anemia

• Hgb <8 g/dL: Interrupt panobinostat until Hgb ≥10 g/dL Restart at reduced dose

Diarrhea

• Moderate (4-6 stools/day): Interrupt panobinostat (and bortezomib) dosing until resolved; restart each drug at same dose
• Severe (≥7 stools/day): Interrupt panobinostat (and bortezomib) dosing until resolved; restart each drug at reduced dose
• Life-threatening (grade 4): Permanently discontinue panobinostat (and bortezomib)

Nausea or vomiting

• Severe nausea (grade 3 or 4): Interrupt until resolved; restart at reduced dose
• Severe/life-threatening vomiting (grade 3 or 4): Interrupt until resolved; restart at reduced dose

Myelosuppression

• Interrupt or reduce panobinostat dose for thrombocytopenia, neutropenia, or anemia according to instructions listed above
• For patients with severe thrombocytopenia, consider platelet transfusions
• Discontinue panobinostat treatment if thrombocytopenia does not improve despite the recommended treatment modifications or if repeated platelet transfusions are required
• In the event of grade 3 or 4 neutropenia, consider dose reduction and/or the use of growth factors (eg, granulocyte colony-stimulating factor [G-CSF])
• Discontinue panobinostat if neutropenia does not improve despite dose modifications, colony-stimulating factor therapy, or severe infection

Gastrointestinal toxicity

• Gastrointestinal toxicity is common during treatment with panobinostat
• Patients who experience diarrhea, nausea, or vomiting may require treatment interruption or dose reduction (see instructions listed above)
• At the first sign of abdominal cramping, loose stools, or onset of diarrhea, patients should be treated with antidiarrheal medication (eg, loperamide)
• Consider and administer prophylactic antiemetics as clinically indicated

Other adverse effects

• For patients experiencing grade 3 or 4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity, the recommendation is the following:
• Grade 2 toxicity recurrence and grade 3 and 4: Omit the dose until recovery to ≤grade and restart treatment at a reduced dose
• Grade 3 or 4 toxicity recurrence: A further dose reduction may be considered once the adverse events have resolved to ≤grade 1

CYP3A4 inhibitors and inducers

• Strong CYP3A4 inhibitors: Reduce panobinostat starting dose to 10 mg
• Strong CYP3A4 inducers: Avoid coadministration; reduces systemic exposure of panobinostat

Hepatic impairment

• Mild: Reduce starting dose to 15 mg
• Moderate: Reduce starting dose to 10 mg
• Severe: Avoid use

Renal impairment

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

 

Dosing Considerations

Multiple myeloma indication is approved under accelerated approval based on progression-free survival; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials

 

Geriatric Dosage & Indications

In clinical trials, 42% of patients were ≥65 yr

Patients older than 65 yr had a higher frequency of selected adverse events and of discontinuation of treatment because of adverse events

The incidence of deaths not related to disease progression was 9% in patients ≥65 yr compared with 5 % in patients <65 yr

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Farydak (panobinostat) adverse (side) effects

>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%)

 

Warnings

Black box warnings

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

 

Contraindications

None

 

Cautions

Severe diarrhea reported in 25%, and diarrhea of any grade reported in 68% (compared with 42% in control arm in clinical trials); monitor hydration status and electrolyte blood levels at baseline and weekly (or more often as clinically required)

Fatal and serious hemorrhage reported

Causes myelosuppression, including severe thrombocytopenia, neutropenia, and anemia; obtain baseline CBC count and monitor weekly during treatment (or more often as clinically required)

Localized and systemic infections, including pneumonia, bacterial infections, invasive fungal infections, and viral infections, reported; severe infections occurred in 31% (including 10 deaths) compared with 24% (including 6 deaths) in the control arm of clinical trials

Hepatic dysfunction, primarily elevations in aminotransferases and total bilirubin, reported; monitor liver function prior to treatment and regularly during treatment

Can cause fetal harm when administered to a pregnant woman

Cardiac toxicities

• Severe and fatal cardiac ischemic events, as well as severe arrhythmias and ECG changes, reported
• Arrhythmias occurred in 12% of those receiving panobinostat compared with 5% of the control arm
• Do not initiate with history of recent MI or unstable angina ECG abnormalities such as ST-segment depression and T-wave abnormalities also occurred more frequently in patients receiving panobinostat compared with the control arm: 22% versus 4% and 40% versus 18%, respectively
• May prolong cardiac ventricular repolarization (QT interval); do not initiate if QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities
• Arrhythmias may be exacerbated by electrolyte abnormalities
• If the QTcF increases to ≥480 msec during treatment, interrupt treatment and correct any electrolyte abnormalities
• If QT prolongation does not resolve, permanently discontinue drug
• Obtain ECG at baseline and periodically during treatment as clinically indicated
• Monitor electrolytes during treatment and correct abnormalities as clinically indicated

 

Pregnancy and 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

Because many drugs are excreted in human milk and because of the potential for serious adverse drug reactions in nursing infants, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

 

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.

 

Pharmacology of Farydak (panobinostat)

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

 

Absorption

Bioavailability: 21%

Peak plasma concentration: 2 hr

 

Distribution

Protein bound: 90%

P-gp substrate

 

Metabolism

Extensively metabolized via various pathways (ie, reduction, hydrolysis, oxidation, glucuronidation)

CYP3A4 accounts for ~40% of hepatic elimination

Substrate of CYP3A4 (predominant); additional contributions from the CYP2D6 and CYP2C19 pathways are minor

In vitro, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B4 contribute to the glucuronidation of panobinostat

 

Elimination

Half-life: 37 hr

Clearance: 160 L/hr (65% variability)

Excretion: 29-51% urine (<2.5% unchanged); 44-77% feces (<3.5% unchanged)

 

Administration

Instructions

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

Counsel patients on the correct dosing schedule, technique of administration, and when to take if dosing adjustments are made

Missed dose

• If a dose is missed, it can be taken up to 12 hr after the specified dose time
• If vomiting occurs, the patient should not repeat the dose, but should take the next usual scheduled dose

 

Monitoring

Monitor the following at baseline and during treatment

CBC count

• Obtain a CBC count before initiating treatment; verify that the baseline platelet count is at least 100 x 10^9/L and the baseline absolute neutrophil count (ANC) is at least 1.5 x 10^9/L
• Monitor the CBC count weekly (or more often as clinically indicated) during treatment

ECg

• Perform an ECG prior to the start of therapy and repeat periodically during treatment as clinically indicated
• Verify that the QTcF is <450 msec prior to treatment initiation
• If the QTcF increases to ≥480 msec, interrupt treatment
• Correct any electrolyte abnormalities
• If QT prolongation does not resolve, permanently discontinue panobinostat
• During the clinical trial, ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles

Serum electrolytes

• Obtain electrolytes, including potassium and magnesium, at baseline and monitor during therapy
• Correct abnormal electrolyte values before treatment
• During the trial, monitoring was conducted prior to the start of each cycle, at Day 11 of cycles 1 to 8, and at the start of each cycle for cycles 9 to 16