Panobinostat Capsules

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

FARYDAK may prolong cardiac ventricular repolarization (QT interval) [see WARNINGS AND PRECAUTIONS]. 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

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]. 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.

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

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.

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].

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].

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, DRUG INTERACTIONS].

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].

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].

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.

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.

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.

Animal Toxicology And/Or Pharmacology

Adverse findings observed in animals and not reported (or reported with low incidence) in patients treated with panobinostat include thyroid, bone marrow, and skin findings. Thyroid hormone changes in oral studies in rats and dogs included decreases in triodothyronine (T3), tetraiodothyronine (T4) and thyroid stimulating hormone (TSH). Histopathology changes of the thyroid included decreases in follicular colloid and epithelial vacuolation, and increases in thyroid follicular hypertrophy. A benign thyroid follicular cell adenoma was also seen in 1 rat in the 26-week study. Bone marrow findings in one or both species included hyperostosis, plasmacytosis, increased number of granulocytic cells, and presence of abnormal cytoplasmic granulation. Osseous metaplasia of the lung and skin hyperplasia and papilloma were observed in dogs in the 39-week study.

Clinical Studies

The efficacy and safety of FARYDAK in combination with bortezomib and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy.

Patients received bortezomib (1.3 mg/m² injected intravenously) with dexamethasone (20 mg) in addition to FARYDAK 20 mg (or placebo), taken orally every other day, for 3 doses per week in Weeks 1 and 2 of each 21-day cycle. Treatment was administered for a maximum of 16 cycles (48 weeks).

A total of 768 patients were randomized in a 1:1 ratio to receive either the combination of FARYDAK, bortezomib, dexamethasone (n=387) or placebo, bortezomib, dexamethasone (n=381), stratified by prior use of bortezomib and the number of prior lines of anti-myeloma therapy. Demographics and baseline disease characteristics were balanced between arms. The median age was 63 years (range 28 to 84); 42% of patients were older than 65 years; 53% of patients were male; Caucasians comprised 65% of the study population, Asians 30%, and blacks 3%. The ECOG performance status was 0 to 1 in 93% of patients. The median number of prior therapies was 1; 48% of patients received 2 or 3 prior lines of therapy. More than half (57%) of the patients had prior stem cell transplantation. The most common prior antineoplastic therapies were corticosteroids (90%), melphalan (80%), thalidomide (53%), cyclophosphamide (47%), bortezomib (44%), and lenalidomide (19%). The median duration of follow-up was 29 months in both arms.

The primary endpoint was progression-free survival (PFS), using modified European Bone Marrow Transplant Group (EBMT) criteria, as assessed by the investigators. In the overall trial population, the median PFS (95% CI) was 12 months (10.3, 12.9) in the FARYDAK, bortezomib, dexamethasone arm and 8.1 months (7.6, 9.2) in the placebo, bortezomib, dexamethasone arm, [HR: 0.63 (95% CI: 0.52, 0.76)]. At the time of interim analysis, overall survival was not statistically different between arms. The approval of FARYDAK was based upon the efficacy and safety in a prespecified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of 2 prior therapies as the benefit:risk appeared to be greater in this more heavily pretreated population than in the overall trial population. Of these 193 patients, 76% of them had received ≥ 2 prior lines of therapy. The median PFS (95% CI) was 10.6 months (7.6, 13.8) in the FARYDAK, bortezomib, and dexamethasone arm and 5.8 months (4.4, 7.1) in the placebo, bortezomib, and dexamethasone arm [HR: 0.52 (0.36, 0.76]. Efficacy results are summarized in Table 6 and the Kaplan- Meier curves for PFS are provided in Figure 1.

Table 6: Efficacy Results from the Multiple Myeloma Trial in Patients who Received Prior Treatment with Bortezomib and an Immunomodulating Agent

Figure 1: Kaplan-Meier Plot of Progression-Free Survival in Patients with Multiple Myeloma who Received Prior Treatment with Both Bortezomib and an Immunomodulatory Agent

In the subgroup of patients who had received prior treatment with both bortezomib and an immunomodulatory agent (n=193), the overall response rate using modified EBMT criteria was 59% in the FARYDAK, bortezomib, and dexamethasone arm and 41% in the placebo, bortezomib, and dexamethasone arm. Response rates are summarized in Table 7.

Table 7: Response Rates

The following adverse reactions are described in detail in other sections of the label:

• Diarrhea [see WARNINGS AND PRECAUTIONS]
• Cardiac Toxicities [see WARNINGS AND PRECAUTIONS]
• Hemorrhage [see WARNINGS AND PRECAUTIONS]
• Myelosuppression [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience

The safety data reflect subject exposure to FARYDAK from a clinical trial, in which 758 subjects with relapsed multiple myeloma received FARYDAK in combination with bortezomib and dexamethasone or placebo in combination with bortezomib and dexamethasone (referred to as the control arm). The median duration of exposure to FARYDAK was 5 months with 16% of patients exposed to study treatment for > 48 weeks.

Serious adverse events (SAEs) occurred in 60% of patients in the FARYDAK, bortezomib, and dexamethasone 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%).

Adverse reactions that led to discontinuation of FARYDAK occurred in 36% of patients. The most common adverse reactions leading to treatment discontinuations were diarrhea, fatigue, and pneumonia.

Deaths occurred in 8% of patients in the FARYDAK arm versus 5% on the control arm. The most frequent causes of death were infection and hemorrhage.

Table 4 summarizes the adverse reactions occurring in at least 10% of patients with ≥ 5% greater incidence in the FARYDAK arm, and Table 5 summarizes the treatment-emergent laboratory abnormalities.

Table 4: Adverse Reactions ( ≥ 10% Incidence and ≥ 5% Greater Incidence in FARYDAK-Arm) in Patients with Multiple Myeloma

Other notable adverse drug reactions of FARYDAK not described above, which were either clinically significant, or occurred with a frequency less than 10% but had a frequency in the FARYDAK arm greater than 2% over the control arm in the multiple myeloma clinical trial are listed below:

Infections and infestations: hepatitis B.

Endocrine disorders: hypothyroidism.

Metabolism and nutrition disorders: hyperglycemia, dehydration, fluid retention, hyperuricemia, hypomagnesemia.

Nervous system disorders: dizziness, headache, syncope, tremor, dysgeusia.

Cardiac disorders: palpitations.

Vascular disorders: hypotension, hypertension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, respiratory failure, rales, wheezing.

Gastrointestinal disorders: abdominal pain, dyspepsia, gastritis, cheilitis, abdominal distension, dry mouth, flatulence, colitis, gastrointestinal pain.

Skin and subcutaneous disorders: skin lesions, rash, erythema.

Musculoskeletal and connective tissue disorders: joint swelling.

Renal and urinary disorders: renal failure, urinary incontinence.

General disorders and administration site conditions: chills.

Investigations: blood urea increased, glomerular filtration rate decreased, blood alkaline phosphatase increased.

Psychiatric disorders: insomnia.

Table 5: Treatment-emergent Laboratory Abnormalities ( ≥ 10% Incidence and ≥ 5% Greater Incidence in FARYDAK-arm) in Patients with Multiple Myeloma

Grade 1 to Grade 4 asthenic conditions (fatigue, malaise, asthenia, and lethargy) were reported in 60% of the patients in the FARYDAK arm compared to 42% of patients in the control arm. Grade ≥ 3 asthenic conditions were reported in 25% of the patients in the FARYDAK arm compared to 12% of patients in the control arm. Asthenic conditions led to treatment discontinuation in 6% of patients in the FARYDAK arm versus 3% of patients in the control arm.

The prespecified sub-group upon which the efficacy and safety of FARYDAK was based had a similar adverse reaction profile to the entire safety population of patients treated with FARYDAK, bortezomib, and dexamethasone.

Read the entire FDA prescribing information for Farydak (Panobinostat Capsules)

• Multiple Myeloma