Special Alerts: Panobinostat lactate is no longer commercially available in the U.S. See the FDA website ([Web]) for information on drugs that have been discontinued. REMS: FDA approved a REMS for panobinostat to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of panobinostat and consists of the following: communication plan. See the FDA REMS page ([Web]). |
Panobinostat lactate, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1, 2
Because this drug is no longer available in the US market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information.
Panobinostat lactate is used in combination with bortezomib and dexamethasone for the treatment of multiple myeloma in patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent.1, 2 Panobinostat has been designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.3 The accelerated approval of panobinostat for this indication is based on progression-free survival; continued FDA approval for this indication may be contingent on verification and description of clinical benefit of panobinostat in confirmatory studies.1
Approval of panobinostat for the labeled indication is based principally on data for a subset of patients who were enrolled in PANORAMA1, a randomized, double-blind, placebo-controlled, phase 3, multicenter study evaluating the efficacy of panobinostat in combination with bortezomib and dexamethasone in 768 patients with relapsed multiple myeloma who had received 1-3 prior therapies.1, 2 Patients with primary refractory or bortezomib-refractory disease and those who had received prior treatment with a deacetylase inhibitor were excluded from the study.2 The median number of prior therapies was 1; 48% of patients enrolled in the study had received 2 or 3 prior therapies, and 57% of patients had undergone prior stem cell transplantation.1, 2 The most common agents used in prior antineoplastic regimens were corticosteroids (90%), melphalan (80%), thalidomide (53%), cyclophosphamide (47%), bortezomib (44%), and lenalidomide (19%).1 The median age of patients in the study was 63 years (range 28-84); 53% of patients were male; 65, 30, and 3% were Caucasian, Asian, and black, respectively; and 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1, 2 Treatment consisted of either the combination of panobinostat, bortezomib, and dexamethasone or the combination of placebo, bortezomib, and dexamethasone administered in 21-day cycles; randomization to these regimens was stratified by prior use of bortezomib and the number of prior therapies.1, 2 Patients received either oral panobinostat (20 mg) or placebo 3 times weekly during weeks 1 and 2 (days 1, 3, 5, 8, 10, and 12) of each 21-day cycle.1, 2 IV bortezomib (1.3 mg/m2) was administered twice weekly during weeks 1 and 2 (days 1, 4, 8, and 11) of cycles 1-8 and once weekly during weeks 1 and 2 (days 1 and 8) of cycles 9-16.1, 2 Oral dexamethasone (20 mg) was administered on the day of and the day after bortezomib administration.1, 2 Treatment was administered for a maximum of 16 cycles (48 weeks).1, 2
In PANORAMA1, the primary end point was progression-free survival, as assessed by investigators using modified European Group for Blood and Marrow Transplantation (EBMT) criteria1, 2; median duration of follow-up was 29 months in both treatment groups.1 Median progression-free survival was 12 months in those who received the combination of panobinostat, bortezomib, and dexamethasone and 8.1 months in those who received the combination of placebo, bortezomib, and dexamethasone;1, 2 overall response rates were 61 and 55%, respectively.2 Overall survival was not significantly different between treatment groups at the time of interim analysis.1, 2 Serious adverse effects (60 versus 42%) and grade 3 or 4 adverse effects (96 versus 82%) occurred more frequently in patients receiving panobinostat, bortezomib, and dexamethasone compared with those receiving placebo, bortezomib, and dexamethasone; grade 3 or 4 diarrhea (25 versus 8%), asthenia or fatigue (24 versus 12%), peripheral neuropathy (18 versus 15%), thrombocytopenia (67 versus 31%), lymphopenia (53 versus 40%), and neutropenia (34 versus 11%) were reported more frequently with the combination of panobinostat, bortezomib, and dexamethasone than with the combination of placebo, bortezomib, and dexamethasone.2
The benefit-to-risk assessment appeared to be more favorable in patients with more heavily pretreated disease.1, 5 In the subgroup of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent and had received a median of 2 prior therapies (76% had received 2 or more prior therapies), median progression-free survival was 10.6 months in those receiving panobinostat, bortezomib, and dexamethasone compared with 5.8 months in those receiving placebo, bortezomib, and dexamethasone.1 In this subgroup of patients, the overall response rate (complete, near complete, and partial responses) was 59% in patients receiving panobinostat, bortezomib, and dexamethasone compared with 41% in those receiving placebo, bortezomib, and dexamethasone.1
Because this drug is no longer available in the US market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information.
Because of the risk of cardiac toxicity, an ECG should be performed prior to initiation of panobinostat therapy to confirm that the QT interval (corrected for heart rate using Fridericia's formula; QTcF) is less than 450 msec.1 In addition, serum concentrations of electrolytes, including potassium and magnesium, should be determined prior to therapy and any abnormalities corrected.1 (See Cardiac Effects under Warnings/Precautions: Warnings, in Cautions.)
Because of the risk of myelotoxicity, the complete blood cell count (CBC) should be determined prior to initiation of therapy to verify that baseline platelet and absolute neutrophil counts (ANCs) are within acceptable limits (at least 100,000/mm3 and 1500/mm3, respectively).1 (See Hematologic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Procedures for proper handling and disposal of antineoplastic agents should be followed.1 Exposure to the contents of panobinostat capsules, including exposure to crushed or broken capsules, should be avoided.1 If such contact with the skin or mucous membranes occurs, the affected areas should be washed thoroughly.1
Restricted Distribution Program
Panobinostat can only be obtained through a limited network of specialty pharmacies.8 Clinicians may contact the manufacturer at 888-669-6682 or [Web] for specific availability information.8
Panobinostat lactate is administered orally once daily on each scheduled day at approximately the same time.1 The drug may be administered without regard to food.1
The manufacturer states that panobinostat lactate capsules should be swallowed whole with a cup of water, and the capsules should not be opened, crushed, or chewed.1
Dosage of panobinostat lactate is expressed in terms of panobinostat.1
When used in combination with bortezomib and dexamethasone for the treatment of multiple myeloma in adults who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, the recommended initial oral dosage of panobinostat is 20 mg given 3 times weekly during weeks 1 and 2 (days 1, 3, 5, 8, 10, and 12) of each 21-day cycle for up to 8 cycles.1 During cycles 1-8, the recommended dosage of IV bortezomib is 1.3 mg/m2 given twice weekly during weeks 1 and 2 (days 1, 4, 8, and 11) of each cycle, and the recommended dosage of oral dexamethasone is 20 mg given 4 times weekly during weeks 1 and 2 (days 1, 2, 4, 5, 8, 9, 11, and 12) of each cycle.1 Continuation of treatment for an additional 8 cycles (cycles 9-16) should be considered for patients who derive clinical benefit from the regimen and do not experience unresolved severe or clinically important toxicity.1 For cycles 9-16, the recommended dosage of panobinostat is the same as in cycles 1-8 (i.e., 20 mg 3 times weekly during weeks 1 and 2 [days 1, 3, 5, 8, 10, and 12] of each 21-day cycle).1 However, during cycles 9-16, the recommended dosage of IV bortezomib is reduced to 1.3 mg/m2 once weekly during weeks 1 and 2 (days 1 and 8) of each cycle, and the recommended dosage of oral dexamethasone is reduced to 20 mg twice weekly during weeks 1 and 2 (days 1, 2, 8, and 9) of each cycle.1 The total duration of treatment may be up to 16 cycles (48 weeks).1
The initial dose of panobinostat should be reduced to 10 mg in patients receiving a potent cytochrome P-450 (CYP) 3A inhibitor (e.g., clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir).1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)
Dosage Modification for Toxicity
Therapy with panobinostat and bortezomib may be temporarily interrupted and subsequent dosage reductions may be required in patients who experience adverse effects.1 If dosage modification of panobinostat is necessary, the dose should be reduced in decrements of 5 mg while maintaining the 3-week treatment cycle.1 If a reduction in dosage to less than 10 mg 3 times weekly is necessary, panobinostat should be discontinued.1
Dosage Modification for GI Toxicity
If grade 2 diarrhea (increase of 4-6 stools per day over baseline) occurs, panobinostat therapy should be interrupted; interruption of bortezomib therapy also should be considered.1 Once diarrhea has resolved, therapy with both drugs may be resumed at the previous dosages.1 If grade 3 diarrhea (increase of 7 or more stools per day over baseline) occurs, or if IV fluids or hospitalization is required, therapy with both panobinostat and bortezomib should be interrupted; once diarrhea has resolved, therapy with both drugs may be resumed at reduced dosages.1 If grade 4 (life-threatening) diarrhea occurs, both drugs should be permanently discontinued.1 (See GI Effects under Warnings/Precautions: Warnings, in Cautions.)
If grade 3 or 4 nausea or vomiting occurs, panobinostat therapy should be interrupted; once nausea and vomiting have resolved, panobinostat therapy may be resumed at a reduced dosage.1
Dosage Modification for Cardiac Toxicity
If the QT interval (corrected for heart rate using Fridericia's formula; QTcF) increases to 480 msec or greater, panobinostat therapy should be interrupted and any electrolyte abnormalities corrected.1 If QT interval prolongation does not resolve, panobinostat should be permanently discontinued.1
Dosage Modification for Hematologic Toxicity
Treatment interruption or dosage reduction of panobinostat is required in patients who experience thrombocytopenia, neutropenia, or anemia.1 Platelet transfusions should be considered in patients with severe thrombocytopenia; if thrombocytopenia does not improve despite the recommended treatment modifications or despite repeated platelet transfusions, panobinostat should be discontinued.1 If grade 3 or 4 neutropenia occurs, dosage reduction and/or use of granulocyte colony-stimulating factors (G-CSFs) should be considered.1 If neutropenia does not improve despite these measures or if severe infection occurs, panobinostat should be discontinued.1
If grade 3 thrombocytopenia (platelet count of 25,000 to less than 50,000/mm3) occurs, panobinostat and bortezomib may be continued at the current dosages, with monitoring of platelet counts performed at least weekly.1 If grade 3 thrombocytopenia is accompanied by bleeding or if grade 4 thrombocytopenia (platelet count less than 25,000/mm3) occurs, therapy with panobinostat and bortezomib should be interrupted and platelet counts monitored at least weekly.1 Once the platelet count has recovered to 50,000/mm3 or greater, panobinostat therapy may be resumed at a reduced dosage.1 Once the platelet count has recovered to 75,000/mm3 or greater, bortezomib therapy may be resumed at the previous dosage if only 1 dose was omitted prior to recovery or at a reduced dosage if 2 or more consecutive doses or 2 or more doses within the same cycle were omitted.1
For grade 3 neutropenia with an ANC of 750-1000/mm3, therapy with panobinostat and bortezomib may be continued at the current dosages.1 Following 2 or more occurrences of grade 3 neutropenia with an ANC of 500-750/mm3, bortezomib may be continued at the current dosage but panobinostat therapy should be interrupted; once ANC has recovered to 1000/mm3 or greater, therapy with panobinostat may be resumed at the previous dosage.1
For grade 3 neutropenia that is accompanied by febrile neutropenia of any grade, therapy with both panobinostat and bortezomib should be interrupted.1 Once febrile neutropenia has resolved and ANC has recovered to 1000/mm3 or greater, therapy with panobinostat may be resumed at a reduced dosage, and bortezomib therapy may be resumed at the previous dosage if only 1 dose was omitted prior to recovery or at a reduced dosage if 2 or more consecutive doses or 2 or more doses within the same cycle were omitted.1
For grade 4 neutropenia (ANC less than 500/mm3), therapy with both panobinostat and bortezomib should be interrupted.1 Once ANC has recovered to 1000/mm3 or greater, therapy with panobinostat may be resumed at a reduced dosage, and bortezomib therapy may be resumed at the previous dosage if only 1 dose was omitted prior to recovery or at a reduced dosage if 2 or more consecutive doses or 2 or more doses within the same cycle were omitted.1
If grade 3 anemia (hemoglobin concentration less than 8 g/dL) occurs, panobinostat therapy should be interrupted.1 Once hemoglobin concentration increases to 10 g/dL or higher, panobinostat therapy may be resumed at a reduced dosage.1
Dosage Modification for Other Toxicity
In patients who experience grade 3 or 4 adverse effects other than thrombocytopenia, neutropenia, or GI toxicity, dosage modification of panobinostat is required.1 For grade 3 or 4 toxicity or for a grade 2 recurrence of such toxicity, panobinostat therapy should be interrupted until the toxicity resolves to grade 1 or less; panobinostat may then be resumed at a reduced dosage.1 In those who experience a grade 3 or 4 toxicity recurrence, further reduction in dosage may be considered once the toxicity has resolved to grade 1 or less.1
The initial dose of panobinostat should be reduced to 15 mg in patients with mild hepatic impairment and 10 mg in patients with moderate hepatic impairment.1 Use of panobinostat should be avoided in patients with severe hepatic impairment.1 Patients should be monitored frequently for adverse effects and dosage should be adjusted as needed for toxicity.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states there are no known contraindications to the use of panobinostat.1
Because this drug is no longer available in the US market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information.
GI toxicity is common in patients receiving panobinostat.1 In the PANORAMA1 study in patients with relapsed multiple myeloma, severe diarrhea occurred in 25% of patients receiving panobinostat in combination with bortezomib and dexamethasone.1, 2 Diarrhea of any grade occurred in 68% of patients receiving the panobinostat-containing regimen, compared with 42% of patients receiving bortezomib and dexamethasone alone.1, 2 Diarrhea can occur at any time in patients receiving panobinostat.1 Thus, the patient's fluid and electrolyte status, including serum concentrations of potassium, magnesium, and phosphate, should be monitored prior to initiation of panobinostat therapy and then weekly (or more frequently as clinically indicated) during treatment; any abnormalities should be corrected to prevent dehydration and electrolyte disturbances.1 Patients who experience diarrhea, nausea, or vomiting may require treatment interruption or dosage reduction.1 (See Dosage Modification for Toxicity under Dosage and Administration: Dosage.) Antidiarrheal therapy (e.g., loperamide) should be initiated at the first sign of abdominal cramping, loose stools, or onset of diarrhea.1 Patients initiating panobinostat therapy should have antidiarrheal agents on hand.1 Prophylactic use of antiemetics should be considered as clinically indicated.1
Severe or fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving panobinostat.1
In the PANORAMA1 study in patients with relapsed multiple myeloma, arrhythmias and cardiac ischemic events occurred in 12 and 4%, respectively, of patients receiving panobinostat in combination with bortezomib and dexamethasone, compared with 5 and 1%, respectively, of patients receiving bortezomib and dexamethasone alone.1 Panobinostat should not be initiated in patients with a history of recent myocardial infarction or unstable angina.1
ECG abnormalities such as ST-segment depression and T-wave abnormalities also occurred more frequently in patients receiving panobinostat in combination with bortezomib and dexamethasone (22 and 40%, respectively) compared with those receiving bortezomib and dexamethasone alone (4 and 18%, respectively).1 Panobinostat may prolong the QT interval.1 In the PANORAMA1 study, prolongation of the QT interval (corrected for heart rate using Fridericia's formula; QTcF) to 451-480 or 481-500 msec occurred in 10.8 or 1.3%, respectively, of patients receiving panobinostat in combination with bortezomib and dexamethasone; no episodes in which the QTcF interval exceeded 500 msec were observed.1 In this study, the maximum increase in the QTcF interval from baseline was 31-60 msec or more than 60 msec in 14.5 or 0.8%, respectively, of patients.1 Pooled clinical data from more than 500 patients who received panobinostat as a single agent for various indications and at various dosages indicated that the QTcF interval exceeded 500 msec in approximately 1% of patients overall and in 5% or more of those receiving a panobinostat dose of 60 mg or higher.1
ECGs should be performed prior to initiation of panobinostat therapy and periodically during treatment as clinically indicated.1 Because arrhythmias may be exacerbated by electrolyte disturbances, serum concentrations of electrolytes, including potassium and magnesium, also should be monitored prior to and during treatment, and any abnormalities should be corrected.1 During the PANORAMA1 study in patients with relapsed multiple myeloma, ECGs were performed at baseline and prior to initiation of each treatment cycle for the first 8 cycles and serum electrolytes were monitored prior to the beginning of each cycle, at day 11 of cycles 1-8, and at the start of each cycle for cycles 9-16.1 Panobinostat should not be initiated in patients with a QTcF interval exceeding 450 msec or clinically important ST-segment or T-wave abnormalities.1 If the QTcF interval increases to 480 msec or greater during treatment, panobinostat therapy should be interrupted and any electrolyte abnormalities corrected.1 Panobinostat should be permanently discontinued if QT interval prolongation does not resolve.1
Other Warnings and Precautions
Serious, sometimes fatal, hemorrhage has been reported in patients receiving panobinostat.1 In the PANORAMA1 study in patients with relapsed multiple myeloma, 5 patients receiving panobinostat in combination with bortezomib and dexamethasone died from a hemorrhagic event, compared with 1 patient receiving bortezomib and dexamethasone alone.1 All 5 panobinostat-treated patients had grade 3 or greater thrombocytopenia at the time of the event.1 Grade 3 or 4 hemorrhage was reported in 4% of patients receiving panobinostat in combination with bortezomib and dexamethasone and 2% of patients receiving bortezomib and dexamethasone alone.1
Panobinostat may cause severe thrombocytopenia, neutropenia, and anemia.1 In the PANORAMA1 study in patients with relapsed multiple myeloma, grade 3 or 4 thrombocytopenia occurred in 67% of patients receiving panobinostat in combination with bortezomib and dexamethasone, compared with 31% of patients receiving bortezomib and dexamethasone alone.1 Patients receiving panobinostat in combination with bortezomib and dexamethasone were more likely to receive a platelet transfusion (33 versus 10%) or to require treatment interruption and/or dosage modification because of thrombocytopenia (31 versus 11%) compared with those receiving bortezomib and dexamethasone alone.1
Severe neutropenia occurred in 34% of patients receiving panobinostat in combination with bortezomib and dexamethasone, compared with 11% of patients receiving bortezomib and dexamethasone alone.1 Neutropenia resulted in treatment interruption and/or dosage modification in 10% of patients receiving the panobinostat-containing regimen.1 Patients receiving panobinostat in combination with bortezomib and dexamethasone were more likely to receive a granulocyte colony-stimulating factor (13 versus 4%) compared with those receiving bortezomib and dexamethasone alone.1
Complete blood cell counts (CBCs) should be monitored prior to initiation of therapy and then weekly (or more frequently as clinically indicated) during treatment.1 CBCs should be monitored more frequently in patients older than 65 years of age because an increased frequency of myelosuppression has been observed in these patients.1 Treatment interruptions or dosage reductions may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration: Dosage.)
Local and systemic infections, including pneumonia, bacterial infections, invasive fungal infections, and viral infections, have been reported in patients receiving panobinostat.1 Severe infections occurred in 31% of patients receiving panobinostat in combination with bortezomib and dexamethasone compared with 24% of patients receiving bortezomib and dexamethasone alone; infections were fatal in 10 patients who received the panobinostat-containing regimen and 6 patients who received bortezomib and dexamethasone alone.1 Infections of all grades occurred at similar frequencies in both treatment groups.1 Panobinostat therapy should not be initiated in patients with active infections.1 Patients should be monitored for signs and symptoms of infection during treatment.1 If infection develops, appropriate anti-infective treatment should be initiated promptly and interruption or discontinuance of panobinostat considered.1
Hepatic dysfunction, principally elevations in aminotransferase and total bilirubin concentrations, has occurred in patients receiving panobinostat.1 Hepatic function should be monitored prior to and regularly during treatment.1 If liver function test abnormalities are observed, dosage modifications may be considered (see Dosage and Administration: Special Populations), and the patient should be monitored until concentrations return to normal or pretreatment values.1
Fetal/Neonatal Morbidity and Mortality
Panobinostat may cause fetal harm; teratogenicity has been demonstrated in animals.1
Pregnancy should be avoided during panobinostat therapy.1 A pregnancy test should be performed in women of childbearing potential prior to initiation of therapy and periodically during treatment.1 Women of childbearing potential who are sexually active should be advised to use effective contraception while receiving panobinostat and for at least 1 month following the last dose of the drug.1 Men who are sexually active should use condoms while receiving panobinostat and for 3 months following the last dose.1 If panobinostat is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Panobinostat may cause fetal harm; teratogenicity has been demonstrated in animals.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
It is not known whether panobinostat is distributed into human milk.1 A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of panobinostat have not been established in pediatric patients.1
In clinical trials evaluating panobinostat in patients with relapsed multiple myeloma, 42% of patients were 65 years of age or older.1 Although no overall differences in efficacy were observed between geriatric patients and younger adults, patients 65 years of age or older had a higher frequency of selected adverse effects, were more likely to discontinue treatment because of adverse effects (45 versus 30%), and had a higher rate of death not related to disease progression (9 versus 5%) compared with younger adults.1 Monitoring for potential toxicity (especially GI toxicity, myelosuppression, and cardiac toxicity) should be performed more frequently in patients older than 65 years of age.1
Safety and efficacy of panobinostat have not been established in patients with hepatic impairment.1 In a pharmacokinetic study in patients with advanced cancer, the area under the concentration-time curve (AUC) of panobinostat was increased by 43% in patients with mild hepatic impairment (bilirubin concentration at or below the upper limit of normal [ULN] and AST concentration exceeding the ULN, or bilirubin concentration more than 1 times but not more than 1.5 times the ULN and any AST concentration) and by 105% in those with moderate hepatic impairment (bilirubin concentration exceeding 1.5 times but not more than 3 times the ULN and any AST concentration).1 Use of panobinostat should be avoided in patients with severe hepatic impairment.1 Patients with mild or moderate hepatic impairment should receive a reduced initial dosage of the drug and should be monitored frequently for adverse effects.1 (See Dosage and Administration: Special Populations.)
In a pharmacokinetic study in patients with advanced cancer and various degrees of renal function, systemic exposure to panobinostat was not substantially altered by mild to severe renal impairment.1, 4 Panobinostat has not been studied in patients with end-stage renal disease or patients undergoing dialysis, and it is not known if panobinostat is dialyzable.1
Adverse effects reported in 10% or more of patients receiving panobinostat in combination with bortezomib and dexamethasone, and at an incidence that is at least 5% higher than that reported with bortezomib and dexamethasone alone, include decreased appetite,1, 2 arrhythmia,1 diarrhea,1, 2 fatigue,1 nausea,1, 2 peripheral edema,1, 2 pyrexia,1, 2 vomiting,1, 2 and weight loss.1, 2
Laboratory abnormalities reported in 10% or more of patients receiving panobinostat in combination with bortezomib and dexamethasone, and at an incidence that is at least 5% higher than that reported with bortezomib and dexamethasone alone, include anemia,1, 2 hyperbilirubinemia,1 hypermagnesemia,1 hyperphosphatemia,1 hypoalbuminemia,1 hypocalcemia,1 hypokalemia,1 hyponatremia,1 hypophosphatemia,1 increased serum creatinine concentrations,1 leukopenia,1, 2 lymphopenia,1, 2 neutropenia,1, 2 and thrombocytopenia.1, 2
Because this drug is no longer available in the US market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information.
Panobinostat is a substrate of cytochrome P-450 (CYP) isoenzyme 3A and, in vitro, has been shown to inhibit CYP isoenzymes 2D6, 2C19, and 3A4 (in a time-dependent manner).1 Panobinostat also is a substrate of P-glycoprotein (P-gp).1
In vitro studies indicate that panobinostat does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, or 2E, nor does it induce CYP isoenzymes 1A1/2, 2B6, 2C8/9/19, or 3A or uridine diphosphate-glucuronosyl transferase (UGT) 1A1.1
In vitro, panobinostat inhibits organic anion transporter (OAT) 3, organic anion transporter protein (OATP) 1B1 and 1B3, and organic cation transporter (OCT) 1 and 2; panobinostat does not inhibit P-gp, breast cancer resistance protein (BCRP), or OAT1.1 Panobinostat does not induce P-gp or multidrug resistance protein (MRP) 2 transporters.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
In patients with advanced cancer, concomitant administration of panobinostat (single 20-mg dose) with the potent CYP3A inhibitor ketoconazole (400 mg daily) increased peak plasma concentration and area under the plasma concentration-time curve (AUC) of panobinostat by 62 and 73%, respectively, compared with administration of panobinostat alone.1, 4, 11 Time to peak plasma concentration was unchanged.1, 11 Dose of panobinostat should be reduced to 10 mg when panobinostat is used concomitantly with a potent CYP3A inhibitor (e.g., clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole).1 Star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice should be avoided, as these foods are known to inhibit CYP3A isoenzymes.1
A decrease in panobinostat exposure is likely if panobinostat is used concomitantly with potent inducers of CYP3A.1 Simulations using a physiologically based pharmacokinetic model suggest that systemic exposure of panobinostat may be decreased by approximately 70% in the presence of a potent CYP3A inducer (e.g., rifampin).1, 4 Concomitant use of panobinostat and potent inducers of CYP3A should be avoided.1
In patients with advanced cancer, panobinostat increased the median peak plasma concentration and AUC of the CYP2D6 substrate dextromethorphan by approximately 80 and 60%, respectively, but the extent of change in dextromethorphan exposure was highly variable.1, 4 Concomitant use of panobinostat with sensitive CYP2D6 substrates (e.g., atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine) or CYP2D6 substrates with a narrow therapeutic index (e.g., thioridazine, pimozide) should be avoided.1 If concomitant use of panobinostat and CYP2D6 substrates cannot be avoided, patients should be monitored frequently for adverse reactions.1
Simulations using a physiologically based pharmacokinetic model suggest that panobinostat may increase exposure of the CYP3A substrate midazolam by less than 10%; the clinical relevance of this finding is unknown.1, 4
Drugs that Prolong QT Interval
Concomitant use of antiarrhythmic agents (e.g., amiodarone, disopyramide, procainamide, quinidine, sotalol) or other drugs known to prolong the QT interval (e.g., chloroquine, clarithromycin, methadone, moxifloxacin, pimozide) with panobinostat is not recommended.1 The manufacturer states that antiemetic agents that are known to prolong the QT interval (e.g., dolasetron, ondansetron, tropisetron) may be used concomitantly with frequent ECG monitoring.1
Although aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility, simulations using a physiologically based pharmacokinetic model suggest that changes in gastric pH will not substantially alter oral absorption of panobinostat.1, 4
Because this drug is no longer available in the US market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information.
Panobinostat, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1, 2 HDAC enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors.1, 6, 9, 10 Overexpression of HDAC enzymes or aberrant recruitment of HDAC enzymes to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones has been observed in some cancer cells.7, 10, 12, 13 Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription.7 Inhibition of HDAC activity allows for the accumulation of acetyl groups on histone lysine residues, resulting in an open chromatin structure and transcriptional activation.1, 10 Panobinostat inhibits the enzymatic activity of HDAC isoforms in classes I, II, and IV at low nanomolar concentrations.1, 5, 6, 9 In vitro, panobinostat causes the accumulation of acetylated histones and other proteins and induces cell cycle arrest and/or apoptosis of some transformed cells.1, 9 Increased levels of acetylated histones have been observed in xenografts from mice treated with panobinostat.1
Panobinostat is extensively metabolized via reduction, hydrolysis, oxidation, and glucuronidation.1 Metabolism by cytochrome P-450 (CYP) isoenzyme 3A accounts for approximately 40% of the total hepatic panobinostat elimination; minor contributions from CYP 2D6 and 2C19 have been observed in vitro.1 In vitro, uridine diphosphate-glucuronosyl transferase (UGT) 1A1, 1A3, 1A7, 1A8, 1A9, and 2B4 contribute to the glucuronidation of the drug.1 Panobinostat is excreted in feces (44-77%) and urine (29-51%), mainly as metabolites; only a small portion of a dose is excreted as unchanged drug (less than 3.5% in feces and less than 2.5% in urine).1 The terminal elimination half-life of panobinostat in patients with advanced cancer is approximately 37 hours.1
Because this drug is no longer available in the US market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information.
Importance of instructing patients to read the manufacturer's medication guide carefully before starting panobinostat therapy and each time the prescription is refilled.1
Importance of advising patients to take panobinostat exactly as prescribed and not to alter the dose or discontinue the drug without first consulting their clinician.1
Importance of advising patients that a missed dose should be taken as soon as possible, up to 12 hours after the scheduled administration time.1 If a dose is vomited, the dose should not be repeated; instead, the next dose should be taken at the regularly scheduled time.1
Importance of swallowing the capsules whole and of not opening, crushing, or chewing capsules.1 If powder from the capsules accidentally contacts the skin or eyes, importance of washing the skin with soap and water or flushing the eyes with water.1
Risk of cardiac toxicity and ECG changes; importance of advising patients to report chest pain or discomfort, changes in heart rate, palpitations, lightheadedness, fainting, dizziness, blue discoloration of lips, shortness of breath, and swelling of lower limbs or skin.1
Risk of thrombocytopenia and bleeding.1 Importance of advising patients to immediately contact their clinician if they experience any episodes or observe any signs or symptoms of bleeding; importance of informing patients that it might take longer than usual for bleeding to stop.1
Importance of advising patients that regular blood tests will be performed to monitor blood cell counts and chemistries.1
Risk of neutropenia and potentially severe and life-threatening infections.1 Importance of advising patients to contact their clinician immediately if they develop a fever or any other signs or symptoms of infection.1
Risk of severe nausea, vomiting, and diarrhea, which may require treatment.1 Importance of advising patients to contact their clinician at the onset of diarrhea, if persistent vomiting occurs, or if signs of dehydration are present, and to consult with their clinician prior to taking medications with laxative properties.1
Risk of fetal harm.1 Importance of advising women of childbearing potential to avoid pregnancy while receiving panobinostat.1 Sexually active women should be advised to use effective contraception while receiving the drug and for at least 1 month after the last dose.1 Sexually active men should be advised to use condoms while receiving panobinostat and for at least 3 months after the last dose.1
Importance of advising women not to breast-feed while taking panobinostat.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1 Importance of avoiding star fruit and pomegranate or grapefruit products.1
Importance of informing patients of other precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of panobinostat is restricted.8 (See Restricted Distribution under Dosage and Administration: General.)
Because this drug is no longer available in the US market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information.
AHFS® Drug Information. © Copyright, 1959-2022, Selected Revisions September 7, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Novartis Pharmaceuticals. Farydak® (panobinostat) capsules prescribing information. East Hanover, NJ; 2015 Feb.
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; 15:1195-206. [PubMed 25242045]
3. Food and Drug Administration. FDA Application: Search Orphan Drug Designattions and Approvals.Rockville, MD. From FDA website. Accessed July 14, 2015. [Web]
4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number205353Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number205353Orig1s000: Summary review. From FDA website. [Web]
6. Richardson PG, Laubach JP, Lonial S et al. Panobinostat: a novel pan-deacetylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma. Expert Rev Anticancer Ther . 2015; 15:737-48. [PubMed 26051506]
7. Cea M, Cagnetta A, Gobbi M et al. New insights into the treatment of multiple myeloma with histone deacetylase inhibitors. Curr Pharm Des . 2013; 19:734-44. [PubMed 23016853][PubMedCentral]
8. Novartis. Farydak (panobinostat) pharmacy network. 2015 Jul. From Novartis for Healthcare Professionals website. [Web]
9. Neri P, Bahlis NJ, Lonial S. Panobinostat for the treatment of multiple myeloma. Expert Opin Investig Drugs . 2012; 21:733-47. [PubMed 22404247]
10. Garnock-Jones KP. Panobinostat: first global approval. Drugs . 2015; 75:695-704. [PubMed 25837990]
11. Hamberg P, Woo MM, Chen LC et al. Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Cancer Chemother Pharmacol . 2011; 68:805-13. [PubMed 21706316][PubMedCentral]
12. Merck & Co., Inc. Zolinza® (vorinostat) capsules prescribing information. Whitehouse Station, NJ; 2013 Apr.
13. Richon VM. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer . 2006; 95:S2-6: [PubMedCentral][Web]