Panobinostat (Farydak) is a high potency histone deacetylase (HDAC) inhibitor that has been approved by the FDA for the treatment of multiple myeloma.

Panobinostat Uses:

• Multiple myeloma:

  • Treatment of multiple myeloma (in combination with bortezomib and dexamethasone) in patients who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.

Panobinostat  (Farydak) Dose in Adults

• Determine QTcF prior to the start of therapy and verify that QTcF <450 msec prior to panobinostat initiation.
• Baseline ANC should be at least 1,500/mm³ and platelets at least 100,000/mm³ prior to treatment.
• Panobinostat is associated with a moderate emetic potential; consider antiemetics to prevent nausea and vomiting.

Panobinostat  (Farydak) Dose in the treatment of Multiple myeloma:

• Adults:

  • Oral: 20 mg once every other day for 3 doses each week during weeks 1 and 2 of a 21-day treatment cycle (eg, Monday, Wednesday, and Friday of weeks 1 and 2 only, rest during week 3) for up to 8 cycles (in combination with bortezomib and dexamethasone);
  • The treatment may be continued (the same schedule for panobinostat; bortezomib and dexamethasone schedules are modified) for an additional 8 cycles in patients experiencing clinical benefit and acceptable toxicity.
  • The total duration of therapy may be up to 16 cycles (48 weeks).

• Missed doses:

  • Missed doses may be taken up to 12 hours after the scheduled time.
  • Do not repeat the dose if vomiting occurs;
  • Patients should take the next usual scheduled dose.

• Dosage adjustment for concomitant therapy:

  • CYP2D6 substrates:

    • Avoid coadministration with sensitive CYP2D6 substrates (eg, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine) or CYP2D6 substrates that have a narrow therapeutic index (eg, thioridazine, pimozide).

  • Strong CYP3A inducers:

    • Avoid concomitant use with strong CYP3A inducers.

  • Strong CYP3A inhibitors:

    • Reduce the starting panobinostat dose to 10 mg with strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole).

Panobinostat Use in Children:

It is not recommended for use in children.

Panobinostat Pregnancy Risk Category: D

• In animal reproduction studies, adverse events were noted.
• Before starting treatment, it is important to get rid of any pregnancy.
• Women with reproductive potential should not get pregnant and should use a contraceptive while on therapy. This is for at least three months after the last dose of panobinostat.
• Condoms are recommended for males in therapy, and at least six months after the last panobinostat dose.

Use of panobinostat while breastfeeding

• It is unknown if panobinostat is absorbed into breast milk.
• The manufacturer suggests that the mother decide whether to stop nursing her infant or discontinue using the drug. This is in consideration of the risk of serious adverse reactions.

Panobinostat  (Farydak) Dose in Kidney Disease:

• CrCl <80 mL/minute:

  • There are no dosage adjustments provided in the drug manufacturer’s labeling.
  • However, based on a pharmacokinetic study of a single 30 mg dose, the renal impairment does not appear to impact panobinostat exposure in patients with mild, moderate, and severe renal impairment (excluding dialysis patients), and initial dosage adjustment is not necessary.

• End-stage renal disease (ESRD) and ESRD on dialysis:

  • There are no dosage adjustments provided in the drug manufacturer’s labeling (has not been studied)
  • The dialyzability of panobinostat is unknown.

Panobinostat (Farydak) Dose in Liver Disease:

• Hepatic impairment prior to treatment:

  • Mild impairment (bilirubin ≤1 times ULN and AST > 1-time ULN or bilirubin >1 to 1.5 times ULN and any AST):

    • Reduce initial dose to 15 mg; monitor frequently for adverse events and adjust the dose as needed for toxicity.

  • Moderate impairment (bilirubin >1.5 to 3 times ULN and any AST):

    • Reduce initial dose to 10 mg; monitor frequently for adverse events and adjust the dose as needed for toxicity.

  • Severe impairment:

    • Avoid use.

• Hepatic impairment during treatment:

  • If liver function tests are abnormal, consider dosage adjustments, and monitor until the liver function returns to normal or baseline.

Common Side Effects of Panobinostat (Farydak):

• Cardiovascular:

  • Abnormal T Waves On Ecg
  • Peripheral Edema
  • Depression Of ST-Segment On Ecg
  • Cardiac Arrhythmia

• Central Nervous System:

  • Fatigue
  • Lethargy
  • Malaise

• Endocrine & Metabolic:

  • Hypocalcemia
  • Hypoalbuminemia
  • Hypophosphatemia
  • Hypokalemia
  • Hyponatremia
  • Hyperphosphatemia
  • Hypermagnesemia
  • Weight Loss

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Decreased Appetite
  • Vomiting

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Lymphocytopenia
  • Leukopenia
  • Neutropenia
  • Anemia

• Hepatic:

  • Hyperbilirubinemia

• Infection:

  • Severe Infection

• Neuromuscular & Skeletal:

  • Weakness

• Renal:

  • Increased Serum Creatinine

• Miscellaneous:

  • Fever

Less Common Side Effects Of Panobinostat (Farydak):

• Cardiovascular:

  • Hypertension
  • Hypotension
  • Orthostatic Hypotension
  • Palpitations
  • Syncope
  • Ischemic Heart Disease
  • ECG Changes
  • Prolonged Q-T Interval On ECG

• Central Nervous System:

  • Chills
  • Dizziness
  • Headache
  • Insomnia

• Dermatologic:

  • Cheilitis
  • Erythema
  • Skin Lesion
  • Skin Rash

• Endocrine & Metabolic:

  • Dehydration
  • Fluid Retention
  • Hyperglycemia
  • Hyperuricemia
  • Hypomagnesemia
  • Hypothyroidism

• Gastrointestinal:

  • Abdominal Distention
  • Abdominal Pain
  • Colitis
  • Dysgeusia
  • Dyspepsia
  • Flatulence
  • Gastritis
  • Gastrointestinal Pain
  • Xerostomia
  • Gastrointestinal Toxicity

• Genitourinary:

  • Urinary Incontinence

• Hematologic & Oncologic:

  • Hemorrhage

• Hepatic:

  • Hepatitis B
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Transaminases
  • Increased Serum Bilirubin

• Infection:

  • Sepsis

• Neuromuscular & Skeletal:

  • Joint Swelling
  • Tremor

• Renal:

  • Increased Blood Urea Nitrogen
  • Mean Glomerular Filtration Rate Decreased
  • Renal Failure

• Respiratory:

  • Cough
  • Dyspnea
  • Rales
  • Respiratory Failure
  • Wheezing

Contraindications to Panobinostat (Farydak):

• The manufacturer's labeling does not list any contraindications.

Warnings and precautions

• Suppression of bone marrow

  • Anemia, severe thrombocytopenia, and neutropenia have all been reported.
  • You may need to interrupt, modify, discontinue, transfusion or granulocyte-stimulating factor support.
  • Check CBC for differential counts at baseline and throughout treatment.
  • Patients over 65 years old may need more frequent monitoring.

• Cardiovascular events: [US Boxed Warn]

  • Patients who received panobinostat have experienced severe and fatal cardiac ischemic episodes, severe arrhythmias and ECG changes.
  • Electrolyte abnormalities can exacerbate arrhythmias.
  • As clinically indicated, obtain ECG and electrolytes at baseline as well as periodically during treatment.
  • ECG abnormalities, such as ST-segment depression or T-wave abnormalities, have been reported.
  • As needed, monitor and correct electrolyte abnormalities.
  • Panobinostat could prolong the QT interval.
  • You should not begin treatment if QTcF is >450 msec, or if you have clinically significant ST-segment abnormalities or T-wave abnormalities.
  • If QTcF rises to >=480msec, interrupt treatment
  • Correct any imbalances in your electrolytes
  • Stop panobinostat permanently if QT prolongation continues.
  • It is not recommended to use QT prolonging medications in conjunction.
  • Patients with unstable angina or recent MI should not be given panobinostat.

• Gastrointestinal events [US Boxed Warning]

  • One-fourth of patients receiving panobinostat were diagnosed with severe diarrhea.
  • You should monitor for these symptoms and start antidiarrheal treatments. Keep panobinostat at bay until you are able to reduce or stop taking panobinostat.
  • Over two-thirds (63%) of patients reported any grade diarrhea. It can happen at any time.
  • Monitor your hydration and serum electrolytes (including magnesium and potassium).
  • Antidiarrheal medication should be available to patients. Patients should begin antidiarrheal medication at the first sign that they feel like they are experiencing diarrhea, loose stool, or cramping.
  • For moderate diarrhea, interrupt panobinostat therapy (4 to 6 stool per day).
  • Panobinostat can cause nausea and vomiting. Antiemetics may be recommended to help prevent this.
  • Some antiemetics may prolong the QT interval (eg dolasetron and ondansetron). This can be combined with regular ECG monitoring.

• Hemorrhage

  • A fatal and serious hemorhage, including grade 3 or 4, has been reported.
  • Patients who suffered hemorhage experienced thrombocytopenia during hemorhage.

• Hepatotoxicity

  • Reports of hepatic dysfunction (transaminase, total bilirubin elevations), have been made.
  • Monitor your liver function before and during treatment.
  • Consider dosage adjustments if liver function tests show abnormalities. Continue monitoring until liver function returns to baseline or normal.
  • Patients with mild-to moderate hepatic impairment should have their initial dose reduced.
  • Patients with severe impairment should be advised not to use this product.

• Infection

  • Both systemic and localized infections have been reported, including pneumonia, invasive fungal infections and viral infections. These infections can be fatal or severe.
  • Patients with active infections should not be treated.
  • During treatment, be aware of any signs or symptoms that could indicate infection.
  • Start appropriate treatment immediately and discontinue panobinostat if you have an infection.

Panobinostat: Drug Interaction

Monitoring Parameters:

• CBC with differential or platelets (before treatment initiation, then every other week, or more frequently if clinically indicated);
• Serum electrolytes including potassium and magnesium were measured before and during treatment. In the clinical trial electrolytes were also monitored after each cycle.
• Liver function tests during treatment and at baseline
• Pregnancy test (to rule out pregnancy before and during treatment);
• ECG (prior treatment initiation, and as often as clinically indicated during treatment);
• Hydration status
• Monitor for gastrointestinal toxicities (e.g., nausea, diarrhea)
• Hemorrhage symptoms and infection

How to administer Panobinostat (farydak)?

• Panobinostat has moderate emetic properties; antiemetics may be used to prevent nausea or vomiting.
• Orally administer the medication on all days.
• You can take it with or without food.
• Take one capsule with a cup water.
• Do not open, crush or chew the capsules.
• Avoid contact with crushed or broken capsules.
• Avoid contact with powder in capsules on the skin or mucous membranes. If you do come into contact, be sure to wash your hands well.

Mechanism of action of Panobinostat (Farydak):

• Panobinostat, a histone-deacetylase inhibitor (HDAC), inhibits HDACs' enzymatic activity and causes increased acetylation.
• The accumulation of acetylated proteins and other proteins causes cell cycle arrest and/or death in some cells.
• Panobinostat is not effective in multiple myeloma when used as a single agent.
• However, it can be combined with dexamethasone and bortezomib to produce synergistic activity.

Protein binding:

• ~90% to plasma proteins

Metabolism:

• more Extensive via reduction, hydrolysis, oxidation, and glucuronidation; CYP3A accounts for about ~40 % of elimination, CYP2D6, and CYP2C19 are minor pathways.

Bioavailability:

• ~21%; AUC is 16% lower (compared with fasting) when administered with a high-fat meal.

Half-life elimination:

• ~37 hours

Time to peak:

• Within 2 hours

Excretion:

• Feces (44% to 77%; <4% as unchanged drug);
• Urine (29% to 51%; <3% as unchanged drug)

International Brands of Panobinostat:

• Farydak

Panobinostat Brand Names in Pakistan:

No Brands Available in Pakistan.