DRUG INTERACTIONS-(summary)

 Strong CYP3A4 inhibitors: Reduce FARYDAK dose.

1. Strong CYP3A4 inducers: Avoid concomitant use with FARYDAK.

2.Sensitive CYP2D6 substrates: Avoid concomitant use with FARYDAK.

3.  Anti-arrhythmic drugs/QT-prolonging drugs: Avoid concomitant

DRUG INTEERACTIONS-

Panobinostat is a CYP3A substrate and inhibits CYP2D6. Panobinostat is a P-glycoprotein (P-gp) transporter system substrate

1. Agents that May Increase FARYDAK Blood Concentrations CYP3A Inhibitors:

Coadministration of FARYDAK with a strong CYP3A inhibitor increased the Cmax and AUC of panobinostat by 62% and 73% respectively, compared to when FARYDAK was given alone 

Reduce dose to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole)

Instruct  patients to avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice because these foods are known to inhibit CYP3A enzymes. \

2 Agents that May Decrease FARYDAK Plasma Concentrations CYP3A Inducers: Coadministration 

ARYDAK with strong CYP3A inducers was not evaluated in vitro or in a clinical trial however, a reduction in panobinostat exposure is likely. An approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A was observed in simulations using mechanistic models.

Therefore, the concomitant use of strong CYP3A inducers should be avoided [see Clinical Pharmacology (12.3)].

3. Agents whose Plasma Concentrations May be Increased by FARYDAK CYP2D6 Substrates:

FARYDAK increased the median Cmax and AUC of a sensitive substrate of CYP2D6 by approximately 80% and 60%, respectively; however this was highly variable

Avoid coadministrating FARYDAK with sensitive CYP2D6 substrates (i.e., atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and venlafaxine) or CYP2D6 substrates that have a narrow therapeutic index (i.e., thioridazine, pimozide). If concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for adverse reactions.

4. Drugs that Prolong QT interval Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that are known to prolong the QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, methadone, moxifloxacin, bepridil and pimozide) is not recommended. Anti-emetic drugs with known QT prolonging risk, such as dolasetron, ondansetron, and tropisetron can be used with frequent ECG monitoring [

BRIEF SUMMARY

PANOBINAST- (Feb- 2015)

Indn-    is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.

Comp-        Capsules: 10 mg, 15 mg, and 20 mg   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 

ADR-    The most common adverse reactions (incidence of at least 20%) in clinical studies are diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting.

CI-   None 

WARNINGS -

 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.

Pat Infom-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.

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Novel Drug Approvals for 2015

1.Name    FARYDAK

2.Active ingredient-    Panobinast

3. Indication-    .. is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.

Date of Approval  2/23/2015

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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.

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

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.

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. 

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Reference ID: 3699607 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

CLINICAL PHARMACOLOGY -

Mechanism of Action FARYDAK is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations.

2. Pharmacodynamics-

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.

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.

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)]. Reference ID: 3699607

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),

USE IN SPECIFIC POPULATIONS-

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 Reference ID: 3699607 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 [see Pregnancy

. 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.

In the randomized clinical trial in patients with relapsed multiple myeloma, no major differences in effectiveness were observed in older patients compared to younger patients.

Adverse reactions leading to permanent discontinuation occurred in 45% of patients =65 years of age in the FARYDAK treatment arm compared to 30% of patients <65 years age in the FARYDAK treatment arm.

Monitor for toxicity more frequently in patients over 65 years of age, especially for gastrointestinal toxicity, myelosuppression, and cardiac toxicity [see Warnings and Precautions (5.1, 5.4)].

6 Hepatic Impairment The safety and efficacy of FARYDAK in patients with hepatic impairment has not been evaluated. In a pharmacokinetic trial, patients with mild (bilirubin =1xULN and AST >1xULN, or bilirubin >1.0 to 1.5x ULN and any AST) or moderate (bilirubin >1.5x to 3.0x ULN, any AST) hepatic impairment (NCI-ODWG criteria) had increased AUC of panobinostat by 43% and 105%, respectively.

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 [see Dosage and Administration (2.4), Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. Reference ID: 3699607

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 of 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.