Panobinostat- Farydak- @- (Feb 2015) - Anti-cancer
Drug Name:Panobinostat- Farydak- @- (Feb 2015) - Anti-cancer
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
Strong CYP3A4 inhibitors: Reduce FARYDAK dose.
Strong CYP3A4 inducers: Avoid concomitant use with FARYDAK.
Sensitive CYP2D6 substrates: Avoid concomitant use with FARYDAK.
Anti-arrhythmic drugs/QT-prolonging drugs: Avoid concomitant use.
Indication:
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
FARYDAK safely and effectively. See full prescribing information for FARYDAK. FARYDAK® (panobinostat) capsules, for oral use
Initial U.S. Approval: 2015
WARNING: FATAL AND SERIOUS TOXICITIES: SEVERE DIARRHEA AND CARDIAC TOXICITIES See full prescribing information for complete boxed warning.
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.
INDICATIONS AND USAGE
FARYDAK, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.
This indication is approved under accelerated approval based on progression free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Proprietary Name- FARYDAK
Established Name- Panobinostat
Applicant- Novartis Pharmaceuticals Corp.
Indication- For the treatment of Patients with Multiple Myeloma(MM)
who have received at least 2 prior Regimens, including
Bortezomib and in Immunomodulatory agent
Approval Date- 2/23/2015
Approved by U.S.FDA on 30-06-2015 (Ref- FDA approved List- 2015)
SUBSEQUENT APPROVAL-
Panobinast in combination with Bortezomib and Desamethasone for
the treatment of Multiple Myeloma who have received at least two prior
regimens, including Bortezomib and and an immunomodulatory agent
As a condition of this accelerated approval FDA requires the sponsor to
conduct a trial to verify and describe the clinical benefit of pantobinostat
for patients with multiple myeloma
Approval Date 2/23/2015
Approved by U.S.FDA as on 30-06-2015 (Ref- FDA approved List- 2015)
NEW MOLECULAR ENTITY AND NEW THERAPEUTIC BIOLOGICAL
PRODUCTS APPROVED FOR 2015
Certain drugs are classified as New molecular Emtities- NME- for FDA review
Many of these products contain active moieties that have not been approved
by FDA previously, either as a single ingredient or as part of a combination
products; these products frequently provide important new therapies for the
patients.
Some drugs are characterized as NMEs for administrative purposes ,but
nonetheless contain certain active moieties in products that have been
previously approved by FDA. For example, CDER classifies biological
products submitted in an application under section 351(a) of the Public
Service Act as NME for purposes of FDA review, regardless of whether
the agency previously approved a related active moiety in a different
product.
FDAs classification of a drug as an -NME- for review purposes is distinct
from FDAs determination of whether a drug is a - New Chemical Entity or - NCE-
within the meaning of the Federal Food,Drug, and Cosmetic Act
No.6
Drug Name - Panobinostat
Active Ingredient- Farydak
Date of approval - 2/23/2015
FDA-approved use - To treat patients with multiple myeloma
Approved by US FDA on 2/23/2015- (Ref- FDA approved List- 2015)
LIST OF NEW DRUG APPROVED FROM 01-01-2016 To TILL DATE
BY NEW DRUG DIVISION - DRUG CONTROLLER GENERAL- INDIA
Sr.No Name of Drug Indication Date of Issue
6. Panobinostat Hard Gelatin 27-05-2016
Capsules 10mg/15mg/20mg
Panobinostat lactate
In combination with Bortezomib and dexamethsone is
indicated for the the treatment of patients with multiple
myeloma, who have received at least 1 prior therapy
Approved by DCG INDIA (Ref- DCGI approved List- 01-01-2016 To Till Date)
Adverse Reaction:
DRUG INTERACTIONS
Strong CYP3A4 inhibitors: Reduce FARYDAK dose.
Strong CYP3A4 inducers: Avoid concomitant use with FARYDAK.
Sensitive CYP2D6 substrates: Avoid concomitant use with FARYDAK.
Anti-arrhythmic drugs/QT-prolonging drugs: Avoid concomitant use.
ADVERSE REACTIONS
The most common adverse reactions (incidence of at least 20%) in clinical studies are diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.
The most common non-hematologic laboratory abnormalities (incidence = 40%) are hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine.
The most common hematologic laboratory abnormalities (incidence =60%) are thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia.
Contra-Indications:
CONTRAINDICATIONS None
WARNINGS AND 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 FARYDAK therapy.
Embryo-Fetal Toxicity: can cause fetal harm. Advise women of the potential hazard to the fetus and to avoid pregnancy while taking FARYDAK.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
FARYDAK, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.
This indication is approved under accelerated approval based on progression free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
DOSAGE AND ADMINISTRATION
20 mg, taken orally once every other day for 3 doses per 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
DOSAGE FORMS AND STRENGTHS-
Capsules: 10 mg, 15 mg, and 20 mg
SUBSEQUENT APPROVAL-
Panobinast in combination with Bortezomib and Desamethasone for
the treatment of Multiple Myeloma who have received at least two prior
regimens, including Bortezomib and and an immunomodulatory agent
As a condition of this accelerated approval FDA requires the sponsor to
conduct a trial to verify and describe the clinical benefit of pantobinostat
for patients with multiple myeloma
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Dosing and Administration
Instruct patients to take FARYDAK exactly as prescribed and not to change their dose or to stop taking FARYDAK unless they are told to do so by their healthcare provider. If a patient misses a dose, advise them to take their dose as soon possible and up to 12 hours after the specified dose time. If vomiting occurs advise the patient not to repeat the dose, but to take the next usual prescribed dose on schedule.
Cardiac Toxicity/Electrocardiographic Changes-
Inform patients to report chest pain or discomfort, changes in heart beat (fast or slow), palpitations, lightheadedness, fainting, dizziness, blue discoloration of lips, shortness of breath, and swelling of lower limbs or skin as these may be warning signs of a heart problem.
Bleeding Risk
Inform patients that FARYDAK is associated with thrombocytopenia. Advise patients to contact their healthcare provider right away if they experience any signs of bleeding and inform patients that it might take longer than usual for them to stop bleeding.
Advise patients of the need to monitor blood chemistry and hematology prior to the start of FARYDAK therapy and periodically thereafter.
Infections- Inform patients of the risk of neutropenia and severe and life-threatening infections.
Instruct patients to contact their physician immediately if they develop a fever and/or any exhibit any signs of infection.
Gastrointestinal Toxicities
Inform patients that FARYDAK can cause severe nausea, vomiting and diarrhea which may require medication for treatment. Advise patients to contact their physician at the start of diarrhea, for persistent vomiting, or signs of dehydration.
Inform patients to consult with their physicians prior to using medications with laxative properties.
Pregnancy
Inform patients that FARYDAK can cause fetal harm. Advise women of reproductive potential to avoid pregnancy while taking FARYDAK. Advise women of reproductive potential to use effective contraception while taking FARYDAK and for at least 1 month after the last dose of the drug.
Advise sexually active men to use condoms while receiving FARYDAK and for at least 3 months following the last dose of the drug. Lactation Advise women not to breastfeed while taking FARYDAK.
Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2015-XX February 2015
Reference ID: 3699607
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
.1.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.
2. Pharmacodynamics-
Cardiac Electrophysiology-
FARYDAK may prolong cardiac ventricular repolarization (QT interval)
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.
3.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.
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.
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.
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
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
.
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.
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
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.
Avoid coadministration of FARYDAK with sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic value
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.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1.Pregnancy Risk Summary- FARYDAK can cause fetal harm when administered to a pregnant woman. Panobinostat was teratogenic in rats and rabbits.
If FARYDAK is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.
2. Lactation Risk Summary
It is not known whether FARYDAK is excreted in human 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.
3. Females and Males of Reproductive Potential-
Embryofetal toxicity including malformations occurred in embryofetal development studies in rats
Pregnancy Testing-
Perform pregnancy testing in women of childbearing potential prior to starting treatment with FARYDAK and intermittently during treatment with FARYDAK.
Contraception Females-
FARYDAK can cause fetal harm. Advise females of reproductive potential to avoid becoming pregnant while taking FARYDAK. Advise sexually-active females of reproductive potential to use effective contraception while taking FARYDAK and for at least 1 month after the last dose of FARYDAK.
Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking FARYDAK [see Use in Specific Populations (8.1)].
Males-
Advise sexually active men to use condoms while on treatment and for 3 months after their last dose of FARYDAK.
4. Pediatric Use-
The safety and efficacy of FARYDAK in children has not been established.
5. Geriatric Use-
In clinical trials of FARYDAK in patients with multiple myeloma, 42% of patients were 65 years of age or older. Patients over 65 years of age had a higher frequency of selected adverse events and of discontinuation of treatment due to adverse events.
In patients over 65 years of age, the incidence of deaths not related to disease progression was 9% in patients =65 years of age compared to 5 % in patients <65.
6. Hepatic Impairment -
The safety and efficacy of FARYDAK in patients with hepatic impairment has not been evaluated.
Reduce the starting dose of FARYDAK in patients with mild or moderate hepatic impairment.
Avoid use in patients with severe hepatic impairment. Monitor patients with hepatic impairment frequently for adverse events
7. Renal Impairment-
Mild [creatinine clearance (CrCl) =50 to <80 mL/min] to severe renal impairment (CrCl <30 mL/min) did not impact the plasma exposure of panobinostat.
FARYDAK has not been studied in patients with end stage renal disease (ESRD) or patients on dialysis. The dialyzability o f panobinostat is unknown
OVERDOSAGE
There is limited experience with overdosage. Expect exaggeration of adverse reactions observed during the clinical trial, including hematologic and gastrointestinal reactions such as thrombocytopenia, pancytopenia, diarrhea, nausea, vomiting and anorexia. Monitor cardiac status including ECGs, and assess and correct electrolytes.
Consider platelet transfusions for thrombocytopenic bleeding. It is not known if FARYDAK is dialyzable.
