Farydak

Name: Farydak

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Farydak Side Effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Panobinostat can cause serious or fatal heart problems. Get emergency medical help if you have chest pain, fast or slow heartbeats, dizziness or fainting, swelling in your legs, or shortness of breath.

Call your doctor at once if you have:

  • severe or ongoing vomiting or diarrhea;
  • pink or brown urine;
  • easy bruising or bleeding, bleeding that will not stop;
  • low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, rapid heart rate, pale skin, feeling tired or short of breath;
  • signs of an electrolyte imbalance--confusion, headache, slurred speech, increased thirst or urination, leg cramps, constipation, fluttering in your chest, numbness or tingling, muscle weakness, loss of coordination, feeling unsteady;
  • liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
  • signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.

Common side effects may include:

  • nausea, vomiting, loss of appetite;
  • diarrhea;
  • fever;
  • swelling in your arms or legs;
  • tired feeling; or
  • low blood cell counts.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Farydak Interactions

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Certain foods may interact with panobinostat and lead to unwanted side effects. Avoid eating star fruit, pomegranate and grapefruit products while taking panobinostat.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Other drugs may interact with panobinostat, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Manufacturer

  • Novartis Pharmaceuticals Corporation

Farydak Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • atomoxetine (Strattera)
  • bepredil (Vascor)
  • boceprevir (Victrelis)
  • chloroquine
  • clarithromycin (Biaxin)
  • conivaptan (Vaprisol)
  • desipramine (Norpramin)
  • dextromethorphan (Delsym)
  • dolasetron(Anzemet)
  • halofantrine (Halfan)
  • indinavir (Crixivan)
  • itraconazole (Onmel, Sporanox)
  • ketoconazole (Nizoral)
  • lopinavir/ritonavir (Kaletra)
  • methadone (Methadose, Diskets)
  • metoprolol (Lopressor)
  • moxifloxacin (Vigamox, Avelox, Moxeza)
  • nebivolol (Bystolic)
  • nefazadone (Serzone)
  • nelfinavir (Viracept)
  • ondansetron (Zupenz, Zofran)
  • perphenazine
  • pimozide (Orap)
  • posaconazole (Noxafil)
  • ritonavir (Norvir, in Kaletra)
  • saquinavir (Fortovase, Invirase)
  • telaprevir (Incivek)
  • telithromycin (Ketek)
  • thioridazine
  • tolterodine (Detrol)
  • tropisetron (Navoban)
  • venlafaxine (Effexor)
  • voriconazole (Vfend)

This is not a complete list of Farydak drug interactions. Ask your doctor or pharmacist for more information.

Farydak FDA Warning

WARNING: FATAL AND SERIOUS TOXICITIES: SEVERE DIARRHEA AND CARDIAC TOXICITIES

Severe diarrhea occurred in 25% of FARYDAK treated patients. Monitor for symptoms, institute anti-diarrheal treatment, interrupt FARYDAK and then reduce dose or discontinue FARYDAK.

Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving FARYDAK. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Panobinostat side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Panobinostat can cause serious or fatal heart problems. Get emergency medical help if you have chest pain, fast or slow heartbeats, dizziness or fainting, swelling in your legs, or shortness of breath.

Call your doctor at once if you have:

  • severe or ongoing vomiting or diarrhea;

  • pink or brown urine;

  • easy bruising or bleeding, bleeding that will not stop;

  • low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, rapid heart rate, pale skin, feeling tired or short of breath;

  • signs of an electrolyte imbalance--confusion, headache, slurred speech, increased thirst or urination, leg cramps, constipation, fluttering in your chest, numbness or tingling, muscle weakness, loss of coordination, feeling unsteady;

  • liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

  • signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.

Common side effects may include:

  • nausea, vomiting, loss of appetite;

  • diarrhea;

  • fever;

  • swelling in your arms or legs;

  • tired feeling; or

  • low blood cell counts.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Introduction

Antineoplastic agent; a histone deacetylase (HDAC) inhibitor.1 2

Actions

  • Inhibits enzymatic activity of HDAC isoforms in classes I, II, and IV at low nanomolar concentrations;1 5 6 9 HDAC enzymes catalyze removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors.1 6 9 10

  • Overexpression of HDAC enzymes or aberrant recruitment of HDAC enzymes to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones observed in some cancer cells.7 10 12 13

  • Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription.7

  • Inhibition of HDAC activity allows for accumulation of acetyl groups on histone lysine residues, resulting in an open chromatin structure and transcriptional activation.1 10

  • In vitro, causes accumulation of acetylated histones and other proteins and induces cell cycle arrest and/or apoptosis of some transformed cells.1 9

How do I store and/or throw out Farydak?

  • Store in the original container at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Farydak is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Farydak or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Farydak. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Contraindications

None

Clinical pharmacology

     Mechanism of Action

Farydak is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone 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. Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat. Panobinostat shows more cytotoxicity towards tumor cells compared to normal cells.

     Pharmacodynamics

Cardiac Electrophysiology

Farydak may prolong cardiac ventricular repolarization (QT interval) [see Warnings and Precautions (5.2)]. In the randomized multiple myeloma trial, QTc prolongation with values between 451 msec to 480 msec occurred in 10.8% of Farydak treated patients. Events with values of 481 msec to 500 msec occurred in 1.3% of Farydak treated patients. A maximum QTcF increase from baseline of between 31 msec and 60 msec was reported in 14.5% of Farydak treated patients. A maximum QTcF increase from baseline of >60 msec was reported in 0.8% of Farydak treated patients. No episodes of QTcF prolongation >500 msec have been reported with the dose of 20 mg Farydak in the randomized multiple myeloma trial conducted in combination with bortezomib and dexamethasone. Pooled clinical data from over 500 patients treated with single agent Farydak in multiple indications and at different dose levels has shown that the incidence of CTC Grade 3 QTc prolongation (QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher.

     Pharmacokinetics

Absorption

The absolute oral bioavailability of Farydak is approximately 21%. Peak concentrations of panobinostat are observed within 2 hours (Tmax) of oral administration in patients with advanced cancer. Farydak exhibits an approximate dose proportional increase in both Cmax and AUC over the dosing range.

Plasma panobinostat Cmax and AUC0–48 were approximately 44% and 16% lower compared to fasting conditions, respectively, following ingestion of an oral Farydak dose 30 minutes after a high-fat meal by 36 patients with advanced cancer. The median Tmax was also delayed by 2.5 hours in these patients.

The aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility [see Description (11)]. Coadministration of Farydak with drugs that elevate the gastric pH was not evaluated in vitro or in a clinical trial; however, altered panobinostat absorption was not observed in simulations using physiologically-based pharmacokinetic (PBPK) models.

Distribution

Panobinostat is approximately 90% bound to human plasma proteins in vitro and is independent of concentration. Panobinostat is a P-gp substrate.

Metabolism

Panobinostat is extensively metabolized. Pertinent metabolic pathways involved in the biotransformation of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. The fraction metabolized through CYP3A accounts for approximately 40% of the total hepatic panobinostat elimination. In vitro, 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

Twenty-nine percent to 51% of administered radioactivity is excreted in urine and 44% to 77% in the feces after a single oral dose of [14C] panobinostat in 4 patients with advanced cancer. Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in feces with the remainder consisting of metabolites.

An oral clearance (CL/F) and terminal elimination half-life (t1/2) of approximately 160 L/hr and 37 hours, respectively, was estimated using a population based pharmacokinetic (pop-PK) model in patients with advanced cancer. An inter-subject variability 65% on the clearance estimate was also reported. Up to 2-fold accumulation was observed with chronic oral dosing in patients with advanced cancer.

Specific Populations

Population pharmacokinetic (PK) analyses of Farydak indicated that body surface area, gender, age, and race do not have a clinically meaningful influence on clearance.

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of panobinostat was evaluated in a phase 1 study in 24 patients with advanced cancer with varying degrees of hepatic impairment. In patients with NCI-CTEP class mild (i.e., Group B) and moderate (i.e., Group C) hepatic impairment, AUC0-inf increased 43% and 105% compared to the group with normal hepatic function, respectively. The relative change in Cmax followed a similar pattern. The effect of severe hepatic impairment was indeterminate in this study due to the small sample size (n=1). A dose modification is recommended for patients with mild and moderate hepatic impairment [see Use in Specific Populations (8.6)].

Renal Impairment: The effect of renal impairment on the pharmacokinetics of panobinostat was assessed in a phase 1 trial of 37 patients with advanced cancer and varying degrees of renal impairment. Panobinostat AUC0–inf in the mild, moderate and severe renal impairment groups were 64%, 99% and 59%, of the normal group, respectively. The relative change in Cmax followed a similar pattern [see Use in Specific Populations (8.7)].

Drug Interactions:

Strong CYP3A Inhibitors: Coadministration of a single 20 mg Farydak dose with ketoconazole (200 mg twice daily for 14 days) increased the Cmax and AUC0–48 of panobinostat by 62% and 73% respectively, compared to when Farydak was given alone in 14 patients with advanced cancer. Tmax was unchanged. A modified starting dose is recommended [see Dose and Administration (2.4), Drug Interactions (7.1)].

Strong CYP3A Inducers: The human oxidative metabolism of panobinostat via the cytochrome P450 system primarily involves CYP3A isozymes. Simulations using PBPK models, predicted an approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A. Avoid coadministration of Farydak with strong CYP3A inducers [see Drug Interactions (7.2)].

CYP2D6 Substrates: Coadministration of a single 60 mg dextromethorphan (DM) dose with Farydak (20 mg once per day, on Days 3, 5, and 8) increased the Cmax and AUC0–∞ of DM by 20% to 200% and 20% to 130% (interquartile ranges), respectively, compared to when DM was given alone in 14 patients with advanced cancer. These DM exposures were extremely variable (CV% >150%). Avoid coadministration of Farydak with sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic index [see Drug Interactions (7.3)].

CYP3A Substrates: Simulations using PBPK models predict that an exposure increase of less than 10% for the sensitive CYP3A substrate midazolam is likely following coadministration with panobinostat. The clinical implications of this finding are not known.

In vitro studies with CYP or UDPglucuronosyltransferase (UGT) substrates:

Panobinostat inhibits CYP2D6, CYP2C19 and CYP3A4 (time-dependent), but does not inhibit CYP1A2, CYP2C8, CYP2C9, and CYP2E. Panobinostat does not induce CYP1A1/2, CYP2B6, CYP2C8/9/19, CYP3A and UGT1A1.

In vitro studies with drug transporter system substrates:

Panobinostat inhibits OAT3, OCT1, OCT2, OATP1B1 and OATP1B3, but does not inhibit P-gp and breast cancer resistant protein (BCRP), or OAT1.

Panobinostat does not induce P-gp and multidrug resistance protein 2 (MRP2) transporters.

Panobinostat Breastfeeding Warnings

Discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: The effects in the nursing infant are unknown.

Highlights for Farydak

Farydak is used to treat a cancer called multiple myeloma. It’s used only after other treatments have failed.

Farydak comes in the form of a capsule you take by mouth.

Farydak is a brand name for the drug panobinostat. It’s not available as a generic drug.

IMPORTANT INFORMATION
  • FDA warning See Details

  • Bleeding See Details

  • Infections See Details

  • Liver problems See Details

What is panobinostat?

This drug is a prescription drug. It comes in the form of a capsule you take by mouth.

This drug is available as the brand-name drug Farydak. It’s not available as a generic drug.

This drug is used as part of a combination therapy. This means you’ll need to take it with other medications, called bortezomib and dexamethasone.

Why it's used

This drug is used to treat multiple myeloma. This is a cancer that affects a type of white blood cells called plasma cells. 

This drug is used only after other treatments have failed.

How it works

This drug belongs to a class of drugs called histone deacetylase inhibitors. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.

More Details

Farydak Side Effects

More common side effects

The more common side effects of Farydak can include:

  • diarrhea

  • tiredness

  • nausea

  • swelling in your legs

  • decreased appetite

  • fever

  • vomiting

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 9-1-1 if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

  • Diarrhea. Symptoms can include:

    • stomach cramps
    • loose stools
    • feeling dehydrated, with symptoms such as tiredness, thirst, or dry mouth
  • Heart problems such as severe arrhythmias. Symptoms can include:

    • a very fast or irregular heartbeat
    • chest pain
    • feeling lightheaded
    • dizziness
    • fainting
    • blue-colored lips
    • shortness of breath
    • swelling in your legs
  • Bleeding. Symptoms can include:

    • blood in your stools, or stools that look black
    • blood in your urine, or urine that is pink or brown
    • blood in your vomit, or vomit that looks like coffee grounds
    • bleeding that lasts longer than normal
    • long-lasting headaches
    • coughing up blood
    • increased bruising
    • dizziness and weakness
    • confusion
    • trouble speaking
  • Infections. Symptoms can include:

    • fever
    • chills
    • cough
    • flu-like symptoms, such as body aches
    • shortness of breath
    • coughing up blood
    • sore body
    • weakness and tiredness
  • Anemia (low red blood cell counts). Symptoms can include:

    • extreme tiredness 
    • pale skin
    • weakness
    • shortness of breath
    • dizziness or feeling lightheaded
    • cold hands and feet
  • Thrombocytopenia (low platelet counts). Symptoms can include:

    • bruising that occurs more easily or more often than normal
    • a rash of pinpoint-sized, reddish-purple spots
    • bleeding from cuts that lasts longer than normal
    • bleeding from your gums or nose
    • blood in your urine or stools
    • menstrual flows (periods) that are heavier than normal
    • tiredness
  • Leukopenia (low white blood cell counts) and neutropenia (low neutrophil counts). Symptoms can include those of infection, such as:

    • fever
    • body aches
    • tiredness
  • Liver problems. Symptoms can include:

    • tiredness and weakness
    • decreased appetite
    • dark-colored urine
    • pain in your upper abdomen (stomach area)
    • yellowing of your skin or the whites of your eyes
Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this information includes all possible side effects. This information is not a substitute for medical advice. Always discuss possible side effects with a healthcare provider who knows your medical history.
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