Important Safety Information

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...+

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Indication

FARYDAK® (panobinostat) capsules, 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.

Safety Profile

Warnings and Precautions

Diarrhea:

  • Severe diarrhea occurred in 25% of FARYDAK treated patients. Diarrhea of any grade occurred in 68% of patients treated with FARYDAK compared to 42% in the control arm.

  • Diarrhea can occur at any time. Monitor patients for hydration status and electrolyte blood levels, including potassium, magnesium and phosphate, at baseline and weekly (or more frequently, as clinically indicated) during therapy, and correct to prevent dehydration and electrolyte disturbances.

  • Institute anti-diarrheal treatment at the first sign of abdominal cramping, loose stools, or onset of diarrhea. Interrupt FARYDAK at onset of moderate diarrhea (4 to 6 stools per day), and then reduce dose. In patients with severe diarrhea, institute anti-diarrheal treatment, interrupt FARYDAK and then reduce dose or discontinue FARYDAK. 

  • Ensure that patients initiating therapy with FARYDAK have anti-diarrheal medications on hand (eg, loperamide).

Cardiac Toxicities:

  • Severe and fatal cardiac ischemic events, severe arrhythmias, and electrocardiogram (ECG) changes have occurred in patients receiving FARYDAK.

  • Arrhythmias occurred in 12% of patients receiving FARYDAK, compared with 5% of patients in the control arm.

  • Cardiac ischemic events occurred in 4% of patients treated with FARYDAK, compared with 1% of patients in the control arm.

  • Electrocardiographic abnormalities such as ST-segment depression and T-wave abnormalities also occurred more frequently in patients receiving FARYDAK than in the control arm: 22% vs 4% and 40% vs 18%, respectively.

  • FARYDAK may prolong cardiac ventricular repolarization (QT interval). Arrhythmias may be exacerbated by electrolyte abnormalities. If during treatment with FARYDAK, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with FARYDAK.

  • Do not initiate FARYDAK treatment in patients with a history of recent myocardial infarction or unstable angina or in patients with a QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities.

  • Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated. Monitor electrolytes during treatment with FARYDAK and correct abnormalities as clinically indicated.

Hemorrhage:

  • In the phase 3 registration trial with patients with relapsed multiple myeloma, 5 patients receiving FARYDAK compared with 1 patient in the control arm died due to a hemorrhagic event; all 5 patients had grade ≥3 thrombocytopenia at the time of the event.

  • Grade 3/4 hemorrhage was reported in 4% of patients treated with FARYDAK and 2% of patients in the control arm. Monitor platelet counts and transfuse as needed.

Myelosuppression:

  • FARYDAK causes myelosuppression, including severe thrombocytopenia, neutropenia, and anemia.  

  • In the clinical trial in patients with relapsed multiple myeloma, 67% of patients treated with FARYDAK developed Grade 3 to 4 thrombocytopenia compared with 31% in the control arm 

  • Thrombocytopenia led to treatment interruption and/or dose modification in 31% of patients receiving FARYDAK, compared with 11% of patients in the control arm.

  • 33% of patients receiving FARYDAK required platelet transfusion, compared with 10% of patients in the control arm.

  • For patients with severe thrombocytopenia, consider platelet transfusions. Discontinue FARYDAK if thrombocytopenia does not improve.

  • Severe neutropenia occurred in 34% of patients treated with FARYDAK, compared with 11% of patients in the control arm. Neutropenia led to treatment interruption and/or dose modification in 10% of patients receiving FARYDAK.

  • Obtain a baseline CBC and monitor the CBC weekly during treatment (or more frequently if clinically indicated or in patients >65 years of age). Dose modifications are recommended for myelosuppression.

Infections:

  • Severe infections occurred in 31% of patients (including 10 deaths) treated with FARYDAK, compared with 24% of patients (including 6 deaths) in the control arm. 

  • FARYDAK treatment should not be initiated in patients with active infections.

  • Monitor patients for signs and symptoms of infections during treatment; if a diagnosis of infection is made, institute appropriate anti-infective treatment promptly and consider interruption or discontinuation of FARYDAK.

Hepatotoxicity:

  • Hepatic dysfunction, primarily elevations in aminotransferases and total bilirubin, occurred in patients treated with FARYDAK.

  • Monitor liver function prior to and regularly during treatment. If abnormal liver function tests are observed, dose adjustments may be considered and the patient should be followed until values return to normal or pretreatment levels. Avoid use in patients with severe hepatic impairment.

Embryo-Fetal Toxicity:

  • FARYDAK can cause fetal harm when administered to a pregnant woman. 

Adverse Reactions Profile

For all patients (N=758) in PANORAMA-11,2

Adverse reactions in either treatment arm1,2,a,b

Adverse Reactions Bar Chart aAdverse Reactions Bar Chart bAdverse Reactions Bar Chart c

  • Adverse reactions that were >10%, in addition to those shown above, were arrhythmia, weight loss, hyperbilirubinemia, and hypermagnesemia1

aFARYDAK® (panobinostat) capsules was studied in PANORAMA-1, a phase 3, randomized, double-blind study. The safety data reflect data in 758 patients with relapsed multiple myeloma who received FARYDAK in combination with BTZ and dex or placebo in combination with BTZ and dex (referred to as the control arm). Patients were randomized to receive FARYDAK or placebo in combination with BTZ (administered via injection twice weekly during the first 8 cycles of therapy) and dex.1
bCommon Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to assess adverse events in the PANORAMA-1 clinical trial.3
cFatigue includes the terms: fatigue, malaise, asthenia, and lethargy.1

Adverse reactions (all grades) leading to discontinuation of treatment in ≥1% of patients treated with FVD3 

Adverse reactions leading to discontinuation table aAdverse reactions leading to discontinuation table b

  • Adverse reactions that led to discontinuation of FARYDAK occurred in 36% of patients1

  • Grade 1-4 asthenic conditions (fatigue, malaise, asthenia, and lethargy) led to treatment discontinuation in 6% of patients treated with FVD vs 3% of patients treated with placebo/BTZ/dex1

Serious adverse events (SAEs) occurred in 60% of patients in the FARYDAK, bortezomib, and dexamethasone arm compared to 42% of patients in the control arm. The most frequent (≥5%) treatment-emergent SAEs reported for patients treated with FARYDAK were pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%).1

Download Management Guidelines

Download A Guide to Managing Adverse Reactions

Contains algorithims showing dose adjustments and management guidelines 

 

 

Management of Selected Adverse Events

ACT PROMPTLY: Manage adverse reactions with dose interruption and/or reduction, or discontinuation

The following algorithms summarize monitoring recommendations, dose adjustment guidelines, and additional therapy considerations. For more information, please see the full Prescribing Information.

  • If dose reduction of FARYDAK is required, the dose should be reduced in decrements of 5 mg (ie, from 20 mg to 15 mg, or from 15 mg to 10 mg). If the dosing of FARYDAK is reduced below 10 mg, given 3 times per week, discontinue FARYDAK. Keep the same treatment schedule (3-week treatment cycle) when reducing dose.

Incidence of diarrhea

  • All grades: 68% with FARYDAK/BTZ/dex vs 42% with placebo/BTZ/dex

  • Grade 3/4: 25% with FARYDAK/BTZ/dex vs 8% with placebo/BTZ/dex 

Guidelines for managing diarrhea: Treatment of diarrhea should begin at the first sign as clinically indicated1

  • Consider use of antidiarrheals1

Guidelines for managing diarrhea

d If the loperamide regimen is inadequate, additional evaluation and treatment should be pursued as medically indicated. Replacement IV fluids and electrolytes may be used as appropriate.
e Exercise clinical judgment to ensure loperamide is safe for patient. Consider factors such as allergies, contraindications, cardiac events, and potential for misuse/abuse. Consider performing a complete workup for infectious causes, other concomitant medication, and dietary modifications. Patients who are diagnosed with an infectious cause of diarrhea should not be given loperamide. See https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program

Incidence of cardiac events

  • Arrythmias:

    • All grades: 12% with FARYDAK/BTZ/dex vs 5% with placebo/BTZ/dex

    • Grade 3/4: 3% with FARYDAK/BTZ/dex vs 2% with placebo/BTZ/dex

  • Cardiac ischemic events: 4% with FARYDAK/BTZ/dex vs 1% with placebo/BTZ/dex

  • Electrocardiographic (ECG) abnormalities

    • ST-segment depression: 22% with FARYDAK/BTZ/dex vs 4% with placebo/BTZ/dex

    • T-wave abnormalities: 40% with FARYDAK/BTZ/dex vs 18% with placebo/BTZ/dex

Monitoring recommendations for cardiac events: Monitor cardiac function before and throughout therapy1 

For additional information, please refer to the bortezomib and dexamethasone prescribing information.

Incidence of thrombocytopenia

  • All grades: 97% with FARYDAK/BTZ/dex vs 83% with placebo/BTZ/dex

  • Grade 3/4: 67% with FARYDAK/BTZ/dex vs 31% with placebo/BTZ/dex 

Guidelines for managing grade 3/4 thrombocytopenia1

  • Consider platelet transfusion for patients with severe thrombocytopenia1

 

Incidence of neutropenia

  • All grades: 75% with FARYDAK/BTZ/dex vs 36% with placebo/BTZ/dex

  • Grade 3/4: 34% with FARYDAK/BTZ/dex vs 11% with placebo/BTZ/dex 

Guidelines for managing Grade 3/4 neutropenia1

  • In the event of Grade 3 or 4 neutropenia, consider the use of growth factors (eg, G-CSF)1

Guidelines for managing Grade 3/4 neutropenia

ANC=Absolute neutrophil count. 

Incidence of nausea

  • All grades: 36% with FARYDAK/BTZ/dex vs 21% with placebo/BTZ/dex

  • Grade 3/4: 6% with FARYDAK/BTZ/dex vs 1% with placebo/BTZ/dex 

Incidence of vomiting

  • All grades: 26% with FARYDAK/BTZ/dex vs 13% with placebo/BTZ/dex

  • Grade 3/4: 7% with FARYDAK/BTZ/dex vs 1% with placebo/BTZ/dex 

Guidelines for managing nausea and vomiting1

  • Consider prophylactic use of antiemetics1

Guidelines for managing nausea and vomiting

Incidence of anemia

  • All grades: 62% with FARYDAK/BTZ/dex vs 52% with placebo/BTZ/dex

  • Grade 3/4: 18% with FARYDAK/BTZ/dex vs 19% with placebo/BTZ/dex 

Guidelines for managing anemia1

Guidelines for managing anemia

Guidelines for managing Grade 3/4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity1

Guidelines for managing Grade 3/4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity

Hb=hemoglobin.

fDose reduction may be necessary.1

References

1. FARYDAK [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2016. 2. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206. 3. Data on file. Clinical study report CLBH589D2308. Novartis Pharmaceuticals Corp; Feb 2014. 

INDICATION 

FARYDAK® (panobinostat) capsules, 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.

IMPORTANT SAFETY INFORMATION 

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.

Diarrhea

  • Severe diarrhea occurred in 25% of patients treated with FARYDAK. Diarrhea of any grade occurred in 68% of patients treated with FARYDAK compared with 42% of patients in the control arm. Diarrhea can occur at any time. Ensure patients have antidiarrheal medications on hand, and initiate antidiarrheal medication at the onset of diarrhea
  • Monitor hydration status and electrolyte blood levels at baseline, and weekly (or more often as clinically indicated) during therapy, and correct to prevent dehydration and electrolyte disturbances
  • Interrupt FARYDAK at the onset of moderate diarrhea (4-6 stools/day)
  • For life-threatening diarrhea (grade 4), permanently discontinue FARYDAK and bortezomib
  • For severe diarrhea (≥7 stools/day), or IV fluids or hospitalization required (grade 3), interrupt FARYDAK and bortezomib until resolved and restart both at reduced doses
  • For moderate diarrhea (4-6 stools/day, grade 2), interrupt FARYDAK until resolved and restart at same dose. Consider interruption of bortezomib until resolved and restart at same dose

Cardiac Toxicities

  • Arrhythmias occurred in 12% of patients treated with FARYDAK compared with 5% of patients in the control arm. Cardiac ischemic events occurred in 4% of patients treated with FARYDAK compared with 1% of patients in the control arm
  • Do not initiate FARYDAK treatment in patients with history of recent myocardial infarction or unstable angina
  • ECG abnormalities such as ST-segment depression and T-wave abnormalities occurred more frequently in patients receiving FARYDAK compared with the control arm: 22% vs 4% and 40% vs 18%, respectively
  • FARYDAK may prolong QT interval. Do not initiate treatment with FARYDAK in patients with a QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities
  • Arrhythmias may be exacerbated by electrolyte abnormalities. If during treatment with FARYDAK, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment. Obtain ECG at baseline and periodically during treatment. Monitor electrolytes during treatment with FARYDAK, and correct abnormalities as clinically indicated

Hemorrhage 

  • Fatal and serious cases of gastrointestinal and pulmonary hemorrhage occurred
  • In the phase 3 registration trial, 5 patients receiving FARYDAK, compared with 1 patient in the control arm, died due to a hemorrhagic event. All 5 patients had grade ≥3 thrombocytopenia at the time of the event
  • Grade 3/4 hemorrhage was reported in 4% of patients treated with FARYDAK and 2% of patients in the control arm
  • Monitor platelet counts and transfuse as needed 

Myelosuppression 

  • FARYDAK causes myelosuppression including severe thrombocytopenia, neutropenia, and anemia. Obtain a baseline CBC, and monitor the CBC weekly during treatment (or more often if clinically indicated or in patients >65 years of age)
  • Thrombocytopenia
    • In the phase 3 registration trial, 67% of patients treated with FARYDAK developed Grade 3/4 thrombocytopenia compared with 31% in the control arm
    • Thrombocytopenia led to treatment interruption and/or dose modification in 31% of patients receiving FARYDAK
    • For patients receiving FARYDAK, 33% required platelet transfusion
    • For patients with platelet count <50 x 109/L with bleeding (grade 3) or <25 x 109/L (grade 4)
      • Interrupt FARYDAK therapy and monitor platelets at least weekly until ≥50 x 109/L, and restart at reduced dose
      • Interrupt bortezomib until thrombocytopenia resolves ≥50 x 109/L
        • If only 1 dose of bortezomib was omitted prior to correction to these levels, restart bortezomib at same dose
        • If ≥2 doses were omitted consecutively, or within the same cycle, restart at a reduced dose
  • For patients with platelet count <50 x 109/L (grade 3), maintain FARYDAK and bortezomib doses and monitor platelet counts at least weekly
  • For patients with severe thrombocytopenia, consider platelet transfusions
  • Discontinue FARYDAK if thrombocytopenia does not improve despite the recommended treatment modifications or if repeated platelet transfusions are required
  • Neutropenia
    • Severe neutropenia occurred in 34% of patients treated with FARYDAK compared with 11% of patients in the control arm
    • Neutropenia led to treatment interruption and/or dose modification in 10% of patients receiving FARYDAK
    • Use of granulocyte-colony stimulating factor (G-CSF) was 13% in patients treated with FARYDAK
    • For patients with ANC <0.5 x 109/L (grade 4)
      • Interrupt FARYDAK and bortezomib therapy until ANC is ≥1.0 x 109/L. Restart FARYDAK at reduced dose
      • If only 1 dose of bortezomib was omitted prior to correction to these levels, restart at same dose. If ≥2 doses of bortezomib were omitted consecutively, or within the same cycle, restart at reduced dose
    • For patients with ANC <1.0 x 109/L (grade 3) and febrile neutropenia (any grade)
      • Interrupt FARYDAK and bortezomib therapy until febrile neutropenia is resolved and ANC >1.0 x 109/L
      • Restart FARYDAK at reduced dose
      • If only 1 dose of bortezomib was omitted prior to correction to these levels, restart at same dose. If ≥2 doses of bortezomib were omitted consecutively, or within the same cycle, restart at reduced dose
    • For patients with ≥2 occurrences of ANC between 0.5 – 0.75 x 109/L (grade 3)
      • Interrupt FARYDAK therapy until ANC ≥1.0 x 109/L, and restart at same dose
      • Maintain bortezomib dose
    • For patients with ANC between 0.75 – 1.0 x 109/L (grade 3)
      • Maintain FARYDAK and bortezomib doses
    • For grade 3 or 4 neutropenia, consider dose reduction and/or the use of growth factors
    • Discontinue FARYDAK if neutropenia does not improve despite dose modifications, CSF, or in case of severe infection
  • Anemia
    • For patients with hemoglobin <8 g/dL (grade 3), interrupt FARYDAK until hemoglobin ≥10 g/dL. Restart at reduced dose

Infections 

  • Severe infections occurred in 31% of patients (including 10 deaths) treated with FARYDAK compared with 24% of patients (including 6 deaths) in the control arm
  • FARYDAK treatment should not be initiated in patients with active infections
  • Monitor patients for signs and symptoms of infections during treatment; if a diagnosis of infection is made, institute appropriate anti-infective treatment promptly and consider interruption or discontinuation of FARYDAK

Hepatotoxicity 

  • Hepatic dysfunction, primarily elevations in aminotransferases and total bilirubin, occurred in patients treated with FARYDAK
  • Monitor liver function prior to and regularly during treatment. If abnormal liver function tests are observed, consider dose adjustments. Follow patient until values return to normal or pretreatment levels
  • Avoid use in patients with severe hepatic impairment
  • Reduce the starting dose of FARYDAK to 15 mg or 10 mg in patients with mild or moderate hepatic impairment, respectively

Embryo-Fetal Toxicity

  • FARYDAK can cause fetal harm when administered to a pregnant woman
  • If FARYDAK is used during pregnancy, or if the patient becomes pregnant while taking FARYDAK, the patient should be apprised of the potential hazard to the fetus
  • 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 3 months after the last dose of FARYDAK
  • Advise sexually active men to use condoms while on treatment, and for at least 6 months after their last dose of FARYDAK

DRUG INTERACTIONS 

  • Reduce dose to 10 mg when coadministered with strong CYP3A inhibitors. Instruct patients to avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice
  • Avoid the concomitant use of strong CYP3A inducers
  • Avoid coadministration with sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic index. If concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for adverse reactions
  • Concomitant use of antiarrhythmic medicines, and other drugs that are known to prolong the QT interval, is not recommended. Antiemetic drugs with known QT-prolonging risk can be used with frequent ECG monitoring

 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 nonhematologic laboratory abnormalities (incidence ≥40%) are hypocalcemia, hypophosphatemia, hypoalbuminemia, hypokalemia, hyponatremia, and increased creatinine. The most common hematologic laboratory abnormalities (incidence ≥60%) are thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia
  • Serious adverse events (SAEs) occurred in 60% of patients in the FARYDAK arm. The most frequent (≥5%) treatment-emergent SAEs reported for patients treated with FARYDAK were pneumonia, diarrhea, thrombocytopenia, fatigue, and sepsis
Please see full Prescribing Information, including Boxed WARNING, for FARYDAK® (panobinostat) capsules.