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...+
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).
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.
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.
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.
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.
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.
FARYDAK can cause fetal harm when administered to a pregnant woman.
For all patients (N=758) in PANORAMA-11,2
Adverse reactions in either treatment arm1,2,a,b
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 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
Contains algorithims showing dose adjustments and management guidelines
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
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 http://www.fda.gov/Safety/MedWatch
Incidence of cardiac events
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
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
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 Grade 3/4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity1
fDose reduction may be necessary.1
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.
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