Panobinostat (trade name Farydak) is an oral histone deacetylase inhibitor (HDAC inhibitor). This class of drugs works by influencing the structure of chromatin, the material that makes up chromosomes. By doing so, HDAC inhibitors can regulate gene expression and protein activity, leading to cell cycle arrest and apoptosis (programmed cell death) in cancer cells.

Panobinostat is specifically approved for use in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent.

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

Before starting panobinostat:

• Check the QTcF (a heart test) and make sure it's less than 450 msec.
• Make sure the ANC (a type of white blood cell count) is at least 1,500 per tiny drop of blood.
• Ensure platelets (cells that help blood clot) are at least 100,000 per tiny drop of blood.
• Panobinostat can make some people feel like throwing up. Consider taking anti-sick pills to prevent this.

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

• Take 20 mg of panobinostat by mouth every other day. This means you take it 3 times in a week.
• Take it only on the 1st and 2nd weeks of a 3-week cycle. For example, take it on Monday, Wednesday, and Friday of those weeks. Don't take it during the 3rd week.
• Do this routine for up to 8 cycles (with two other drugs: bortezomib and dexamethasone).
• If the treatment is working and side effects are okay, you can continue the same routine for another 8 cycles. This means treatment can last up to 16 cycles or 48 weeks (almost a year).

If You Forget a Dose:

• If you miss taking panobinostat, you can take it up to 12 hours after when you were supposed to.
• If you vomit after taking it, don't take another dose. Just wait and take the next scheduled dose as usual.

Dosage adjustment for concomitant therapy:

• CYP2D6 Drugs: Don't take panobinostat with certain drugs processed by the CYP2D6 enzyme. Examples of these drugs are atomoxetine, desipramine, and metoprolol. Also, avoid drugs with a small safety margin, like thioridazine and pimozide.
• Strong CYP3A Boosters: Don't take panobinostat with drugs that strongly boost the CYP3A enzyme.
• Strong CYP3A Blockers: If you're taking drugs that block the CYP3A enzyme, reduce the starting dose of panobinostat to 10 mg. Examples of these blockers are ketoconazole, ritonavir, and clarithromycin.

Panobinostat Use in Children:

It is not recommended for use in children.

Panobinostat Pregnancy Risk Category: D

• Studies on animals showed problems related to reproduction.
• Before starting the treatment, it's important to make sure a woman is not pregnant.
• Women who can become pregnant should not get pregnant while on this treatment. They should use effective birth control during treatment and for 3 months after their last dose.
• Men should use condoms during treatment and for 6 months after their last dose of panobinostat.
• Basically, both men and women need to be careful about preventing pregnancy when taking panobinostat, because it might cause harm to a baby.

Use of panobinostat while breastfeeding

• We don't know if panobinostat gets into breast milk.
• Because it might cause severe problems for a baby if it does, it's suggested to either stop breastfeeding or stop taking the drug.
• When making a decision, think about how important the treatment is for the mother.

Panobinostat (Farydak) Dose in Kidney Disease:

For those with reduced kidney function (CrCl <80 mL/minute):

• The manufacturer doesn't give specific instructions for dosage changes.
• A study showed that having mild, moderate, or severe kidney issues (excluding those on dialysis) doesn't seem to change how the body handles panobinostat after a single 30 mg dose. So, you can start with the regular dose (Sharma 2015).

For those with end-stage kidney disease (ESRD) or on dialysis:

• The manufacturer doesn't provide guidance on dosage changes because they haven't studied it in these patients.
• We also don't know if panobinostat can be removed from the body during dialysis.

Panobinostat (Farydak) Dose in Liver Disease:

Mild liver problems:

• Signs: Your bilirubin (a liver enzyme) is up to the normal limit, and another liver enzyme (AST) is above the normal. Or, your bilirubin is a little above normal, but AST can be any level.
• Action: Start with a 15 mg dose of panobinostat. Watch closely for any side effects and adjust the dose if needed.

Moderate liver problems:

• Signs: Your bilirubin is more than 1.5 times but up to 3 times the normal limit, and AST can be any level.
• Action: Start with a 10 mg dose. Watch closely for side effects and adjust if necessary.

Severe liver problems:

• Action: Don't use panobinostat.

If Liver Issues Arise During Treatment:

• If your liver tests show problems while you're on panobinostat, think about adjusting the dose. Keep checking and adjusting until your liver is back to how it was before or reaches a normal state.

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 doesn't list any specific conditions or factors that would make it unsafe to use panobinostat.

Warnings and precautions

Suppression of bone marrow

• Panobinostat can severely reduce the number of blood cells, leading to low platelet, white blood cell, and red blood cell counts.
• This might mean you need to pause the treatment, change the dose, stop it entirely, or get additional treatments like blood transfusions.
• It's crucial to regularly check your blood cell levels, especially when you start.
• If you're over 65, you might need to get checked even more often.

Cardiovascular events: [US Boxed Warn]

• Panobinostat can cause serious heart problems, some of which can be fatal.
• These issues include decreased blood flow to the heart, abnormal heart rhythms, and changes in ECG readings.
• It's essential to get an ECG and check your body's salt levels before starting and during treatment.
• If the ECG shows specific changes or if your QT interval (a measure on the ECG) is too long, you might need to stop taking panobinostat.
• Make sure to adjust any abnormal salt levels in your body.
• Don't take panobinostat if you've recently had a heart attack or chest pain.
• Also, avoid taking it with other medicines that can affect your heart's rhythm.

Gastrointestinal events [US Boxed Warning]

• Panobinostat can cause severe diarrhea in about a quarter of the people who take it.
• If you have diarrhea, even if it's not too severe, it's essential to monitor it closely, use anti-diarrhea medicine, and maybe even stop taking Panobinostat or reduce the dose.
• Many patients also experience any-grade diarrhea, so it can happen at any time during treatment.
• Keep an eye on your fluid levels and certain minerals in your blood, like magnesium, potassium, and phosphate.
• Make sure to have anti-diarrhea medicine on hand and use it at the first sign of diarrhea.
• If you have moderate diarrhea (4 to 6 loose stools per day), pause Panobinostat treatment.
• This medicine can also make you feel nauseous and vomit, so you might want to take anti-nausea medication.
• Be aware that some anti-nausea medicines can affect your heart rhythm, so your doctor might want to monitor your heart closely if you use them.

Hemorrhage

• Panobinostat can cause serious bleeding, sometimes leading to death.
• This serious bleeding happens especially in people who have low platelet counts.

Hepatotoxicity

• Panobinostat can affect the liver, causing it to not work properly.
• Before and while you're on the medication, your doctor will check your liver's health.
• If there's a problem with your liver while on the drug, you might need to adjust the dose and keep checking until your liver gets better.
• If you already have mild or moderate liver problems, you should start with a lower dose of Panobinostat.
• If you have serious liver issues, it's best to avoid the drug altogether.

Infection

• Panobinostat can increase the risk of getting infections, some of which can be severe or even deadly.
• This includes different types of infections like pneumonia, bacterial, fungal, and viral infections.
• Don't start the medication if you currently have an infection.
• While on the drug, watch out for any signs or symptoms of getting sick.
• If you do get an infection, get treated right away, and think about pausing or stopping the Panobinostat.

Panobinostat: Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
ARIPiprazole	CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
CYP2D6 Substrates (High risk with Inhibitors)	Panobinostat may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Dolasetron	May enhance the arrhythmogenic effect of Panobinostat.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Granisetron	May enhance the arrhythmogenic effect of Panobinostat.
Haloperidol	QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTcprolonging effect of Haloperidol.
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Ondansetron	May enhance the arrhythmogenic effect of Panobinostat.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Perhexiline	CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline.
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
QT-prolonging Agents (Highest Risk)	QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Leflunomide	Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
MiFEPRIStone	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.
St John's Wort	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Panobinostat.
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Grapefruit Juice	May increase the serum concentration of Panobinostat.
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Pomegranate	May increase the serum concentration of Panobinostat.
Star Fruit	May increase the serum concentration of Panobinostat.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.

Monitoring Parameters:

Blood Tests:

• Before starting and then weekly (or more if needed) during treatment:
  • Complete Blood Count (CBC) with differential
  • Platelet count

Electrolyte Levels:

• Before and during treatment:
  • Potassium
  • Magnesium
• (In a clinical trial, these were checked at specific times during the treatment cycles.)

Liver Health:

• Check liver function before starting and regularly while on treatment.

Pregnancy Checks:

• For women who could become pregnant:
  • Make sure you're not pregnant before and at times during the treatment.

Heart Health:

• Electrocardiogram (ECG) check:
  • Before starting and then when needed during treatment.

Hydration:

• Monitor fluid levels in the body.

Gut Health:

• Watch out for:
  • Diarrhea
  • Feeling nauseous
  • Vomiting

Signs of Other Problems:

• Look out for signs of bleeding and infections.

How to administer Panobinostat (farydak)?

• Nausea and Vomiting:
  • Panobinostat can make some people feel like throwing up. Think about taking anti-sick pills to prevent this.
• How to Take It:
  • Take the pill by mouth around the same time when it's scheduled.
  • You can take it with or without food.
  • Drink a full glass of water with the pill.
  • Don't open, crush, or chew the pill.
• Handling the Capsule:
  • Be careful not to break the capsule.
  • If the powder from inside touches your skin or the inside of your mouth or nose, wash it off right away.

Mechanism of action of Panobinostat (Farydak):

• Panobinostat is a drug that works by blocking certain enzymes called HDACs.
• When these enzymes are blocked, it leads to changes in proteins in our cells, which can stop the growth of some cancer cells or even make them die.
• Panobinostat doesn't work very well on its own against multiple myeloma (a type of cancer), but when it's used together with other drugs like bortezomib and dexamethasone, they work better together and have a stronger effect against the cancer.

Protein Binding:

• About 90% of Panobinostat sticks to proteins in the blood.

Metabolism (How it's broken down):

• The body mainly breaks it down through various processes.
• The CYP3A enzyme handles about 40% of this breakdown.
• Other enzymes like CYP2D6 and CYP2C19 play smaller roles.

Absorption:

• About 21% of the drug is absorbed into the body.
• If you take it with a high-fat meal, the amount the body absorbs drops by 16% compared to taking it on an empty stomach.

Half-life (How long it stays in the body):

• It takes about 37 hours for half of the drug to leave your body.

Time to Maximum Effect:

• It reaches its highest level in the blood within 2 hours of taking it.

How it Leaves the Body:

• Feces: Between 44% and 77% is excreted through poop. Less than 4% comes out as the unchanged drug.
• Urine: Between 29% and 51% is excreted through pee. Less than 3% comes out as the unchanged drug.

International Brands of Panobinostat:

• Farydak

Panobinostat Brand Names in Pakistan:

Not Available.