FARYDAK

Small Molecule Antineoplastic Histone Deacetylase (HDAC) Inhibitors

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Oral Administration Oral Solid Formulations

Swallow capsules whole with a full glass of water; do not open, crush, or chew capsules.
Administer the dose at approximately the same time every day; panobinostat may taken with or without food.
Avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice.
Avoid direct contact of powder within capsule with skin or mucous membranes; wash area thoroughly if contact occurs.
Healthcare personnel or caregivers should avoid exposure to crushed and/or broken capsules.
If a dose is missed, it may be taken up to 12 hours after the time the dose was scheduled.
If vomiting occurs after the dose, skip that dose; the next dose should be taken at the regularly scheduled time.

Severe

thrombocytopenia / Delayed / 67.0-67.0
lymphopenia / Delayed / 53.0-53.0
neutropenia / Delayed / 34.0-34.0
infection / Delayed / 31.0-31.0
diarrhea / Early / 25.0-25.0
asthenia / Delayed / 0-25.0
malaise / Early / 0-25.0
fatigue / Early / 0-25.0
lethargy / Early / 0-25.0
leukopenia / Delayed / 23.0-23.0
hypophosphatemia / Delayed / 20.0-20.0
hypokalemia / Delayed / 18.0-18.0
anemia / Delayed / 18.0-18.0
hyponatremia / Delayed / 13.0-13.0
atrial flutter / Early / 0-12.0
bradycardia / Rapid / 0-12.0
atrial fibrillation / Early / 0-12.0
respiratory arrest / Rapid / 0-12.0
cardiac arrest / Early / 0-12.0
ventricular tachycardia / Early / 0-12.0
atrial tachycardia / Early / 0-12.0
renal failure (unspecified) / Delayed / 0-10.0
vomiting / Early / 7.0-7.0
nausea / Early / 6.0-6.0
hypermagnesemia / Delayed / 5.0-5.0
hypocalcemia / Delayed / 5.0-5.0
bleeding / Early / 4.0-4.0
supraventricular tachycardia (SVT) / Early / 0-3.0
anorexia / Delayed / 3.0-3.0
hypoalbuminemia / Delayed / 2.0-2.0
peripheral edema / Delayed / 2.0-2.0
weight loss / Delayed / 2.0-2.0
hyperbilirubinemia / Delayed / 1.0-1.0
fever / Early / 1.0-1.0
cardiotoxicity / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known

Moderate

hyperphosphatemia / Delayed / 27.0-27.0
QT prolongation / Rapid / 0-12.0
sinus tachycardia / Rapid / 0-12.0
hypotension / Rapid / 0-10.0
hypertension / Early / 0-10.0
orthostatic hypotension / Delayed / 0-10.0
palpitations / Early / 0-10.0
dehydration / Delayed / 0-10.0
colitis / Delayed / 0-10.0
gastritis / Delayed / 0-10.0
hypomagnesemia / Delayed / 0-10.0
elevated hepatic enzymes / Delayed / 0-10.0
hepatitis / Delayed / 0-10.0
fluid retention / Delayed / 0-10.0
erythema / Early / 0-10.0
skin ulcer / Delayed / 0-10.0
urinary incontinence / Early / 0-10.0
hypothyroidism / Delayed / 0-10.0
hyperglycemia / Delayed / 0-10.0
hyperuricemia / Delayed / 0-10.0
wheezing / Rapid / 0-10.0
dyspnea / Early / 0-10.0

Mild

cheilitis / Delayed / 0-10.0
xerostomia / Early / 0-10.0
dyspepsia / Early / 0-10.0
abdominal pain / Early / 0-10.0
flatulence / Early / 0-10.0
insomnia / Early / 0-10.0
syncope / Early / 0-10.0
dizziness / Early / 0-10.0
tremor / Early / 0-10.0
headache / Early / 0-10.0
dysgeusia / Early / 0-10.0
rash / Early / 0-10.0
chills / Rapid / 0-10.0
cough / Delayed / 0-10.0

Dehydration, diarrhea, nausea/vomiting

Severe gastrointestinal toxicity (e.g., diarrhea, nausea/vomiting) has been reported in patients who received panobinostat. Dehydration may occur. Monitor patient hydration status at baseline and at least weekly during therapy; ensure the patient has adequate hydration prior to and during therapy. All patients should have an anti-diarrheal medication (e.g., loperamide) available prior to starting therapy; instruct patients to start the anti-diarrheal medication at the first sign of abdominal cramping and/or loose stools. Consider administering prophylactic anti-emetic medications. Therapy interruption, a panobinostat dose adjustment, and/or drug discontinuation may be necessary in patients who develop gastrointestinal toxicity.

Angina, apheresis, AV block, bradycardia, cardiac arrhythmias, cardiomyopathy, cardiotoxicity, celiac disease, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

Cardiotoxicity (i.e., severe ischemic events, cardiac arrhythmias, and electrocardiogram (ECG) changes) has occurred in patients who received panobinostat. Avoid panobinostat use in patients with a history of recent myocardial infarction or unstable angina and in patients with baseline QT prolongation (QTcF 450 milliseconds or greater), ST-segment depression, or T-wave abnormalities. Patients with long QT syndrome may be at increased risk for serious QT prolongation or other heart problems. Obtain an ECG at baseline and periodically during treatment. In a clinical trial in patients with multiple myeloma, ECGs were performed at baseline and prior to starting each cycle for the first 8 cycles. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue therapy if the QT prolongation does not resolve. Use panobinostat with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Electrolyte imbalance

Electrolyte abnormalities may result from severe gastrointestinal toxicity and dehydration caused by panobinostat therapy. These abnormalities may increase the risk of arrhythmias. Monitor serum electrolytes (e.g., potassium, magnesium, phosphate) prior to starting therapy, periodically during therapy, and as clinically indicated; correct any electrolyte imbalance. In a clinical trial in patients with multiple myeloma, serum electrolytes were obtained prior to the start of each treatment cycle, at day 11 of cycles 1 to 8, and at the start of each cycle for cycles 9 to 16. Certain electrolyte abnormalities (i.e., hypomagnesemia, hypokalemia, hypocalcemia) may increase the risk of prolonging the QT interval when using panobinostat.

FARYDAK

Rx

Histone deacetylase inhibitor
Previously approved treatment under the accelerated drug approval process for relapsed/ refractory multiple myeloma; the FDA withdrew approval for this indication due to lack of required confirmatory studies
Boxed warning for severe diarrhea and cardiac toxicities; while studied for other oncology uses in clinical trials, the manufacturer discontinued the drug from the U.S. market

For the treatment of multiple myeloma in patients who have received at least 2 prior therapies (including bortezomib and an immunomodulatory agent), in combination with bortezomib and dexamethasone.
NOTE: Panobinostat has been designated as an orphan drug by the FDA.
NOTE: The manufacturer voluntarily withdrew panobinostat from the U.S. market in November 2021 when it was unable to perform the post-approval clinical studies required to confirm a clinical benefit which was a condition of the accelerated approval process. Oral dosage Adults

20 mg orally once every other day for 3 doses per week (on days 1, 3, 5, 8, 10, and 12) for the first 2 weeks of each 21-day cycle. Continue treatment for up to 8 cycles; consider giving up to an additional 8 cycles (maximum of 16 treatment cycles) in patients who experience clinical benefit without unresolved severe or medically significant toxicity. Administer in combination with bortezomib (cycles 1 to 8: 1.3 mg/m2 on days 1, 4, 8, and 11; cycles 9 to 16: 1.3 mg/m2 on days 1 and 8) and dexamethasone (cycles 1 to 8: 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12; cycles 9 to 16: 20 mg orally on days 1, 2, 8, and 9). Avoid concomitant use with strong CYP3A4 inducers; a dose reduction is required if panobinostat is co-administered with a strong CYP3A4 inhibitor. Therapy interruption, a dose adjustment, and/or drug discontinuation may be necessary if severe toxicity occurs. At a median follow-up time of 6.47 months, the median progression-free survival time (primary endpoint) was significantly improved in patients with relapsed or relapsed and refractory multiple myeloma who received panobinostat, bortezomib, and dexamethasone compared with placebo, bortezomib, and dexamethasone (11.99 months vs. 8.08 months; hazard ratio (HR) = 0.63; 95% CI, 0.52 to 0.76; p < 0.0001) in a multinational, randomized, phase III trial (n = 768; the PANORAMA-1 trial). Patients (median, 63 years; range, 56 to 69 years) in this study had received 1 to 3 prior therapies; about 57% of patients had previously received a stem-cell transplantation. At the final analysis, the median overall survival time was not significantly improved in the panobinostat arm in the overall study population (40.3 months vs. 35.8 months; HR = 0.94; 95% CI, 0.78 to 1.14) or in a subpopulation of patients (n = 147) who received at least 2 previous regimens including bortezomib and an immunomodulatory drug (25.5 months vs. 19.5 months; HR = 1.01; 95% CI, 0.68 to 1.5). Crossover from the placebo arm to the panobinostat arm was not permitted in this study. Subsequent multiple myeloma therapy was given in 38% of patients in the panobinostat arm and 49% of patients in the placebo arm; in the subpopulation of patients who received at least 2 previous regimens, subsequent therapy was given in 36% and 66% of patients, respectively.

For the treatment of cutaneous T-cell lymphoma (CTCL)† in patients who have received at least 2 prior systemic therapies.
NOTE: The FDA has designated panobinostat as an orphan drug for the treatment of cutaneous T-cell lymphoma
Oral dosage Adults

20 mg orally on 3 days per week (i.e., Monday-Wednesday-Friday); continue treatment in 28-day cycles until disease progression, drug intolerance, or drug discontinuation. The median duration of panobinostat therapy was 3 months (range, 0.2 to 29.6 months) in patients with prior bexarotene exposure and 3.3 months (range, 0.2 to 26.8 months) in patients who were bexarotene naive in a multicenter, nonrandomized, phase II trial (n = 139).

†Indicates off-label use

Hepatic Impairment

Mild hepatic impairment (bilirubin level 1-time the upper limit of normal (ULN) or less with an AST level greater than 1-time the ULN OR a bilirubin level greater than 1 to 1.5 times the ULN with any AST level) at baseline: reduce the starting dose to 15 mg PO.
Moderate hepatic impairment (bilirubin level greater than 1.5 to 3-times the ULN with any AST) at baseline: reduce the starting dose to 10 mg PO.
Severe hepatic impairment at baseline: use not recommended.
Treatment-Related Hepatotoxicity:
If dose reduction is required, reduce panobinostat in increments of 5 mg (from 20 mg to 15 mg or from 15 mg to 10 mg) and keep the same treatment schedule (dose given on days 1, 3, 5, 8, 10, and 12 of each 21-day cycle). Discontinue therapy if the dose needs to be reduced below 10 mg.
Grade 3 and 4 toxicity or recurrent grade 2 toxicity: hold doses until recovery to grade 1 toxicity or less; restart panobinostat at a reduced dose.
Recurrent grade 3 or 4 toxicity: hold doses until recovery to grade 1 toxicity or less; consider another hold doses dose reduction.

Renal Impairment

No dose adjustment of panobinostat appears necessary in patients with mild (creatinine clearance (CrCl), 50 to 80 mL/min) to severe (CrCl, less than 30 mL/min) renal impairment based on a pharmacokinetic assessment in a phase I study. Panobinostat has not been evaluated in patients with end stage renal disease or patients on dialysis. The dialyzability of panobinostat is not known.

Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with panobinostat may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Panobinostat is a moderate inhibitor of CYP2D6.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Acetaminophen; Dextromethorphan: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with panobinostat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of panobinostat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If panobinostat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Panobinostat is a moderate inhibitor of CYP2D6.
Adagrasib: (Major) Avoid concomitant use of adagrasib and panobinostat due to the potential for increased panobinostat exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, reduce the starting dose of panobinostat to 10 mg and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Panobinostat is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased the AUC of panobinostat by 73%.
Alfuzosin: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include alfuzosin.
Amiodarone: (Major) Concomitant use of panobinostat and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Coadministration of amisulpride and panobinostat is not recommended due to the potential for additive QT prolongation. Amisulpride causes dose- and concentration- dependent QT prolongation. Panobinostat can cause QT prolongation.
Amitriptyline: (Major) The co-administration of panobinostat with tricyclic antidepressants such as amitriptyline is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Amoxicillin; Clarithromycin; Omeprazole: (Major) The co-administration of panobinostat with clarithromycin is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Clarithromycin is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. This interaction may be relevant to combination products containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole (Prevpac) and amoxicillin; clarithromycin; omeprazole (Omeclamox-Pak) triple therapy packs.
Anagrelide: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include anagrelide.
Apalutamide: (Major) Avoid the concomitant use of panobinostat and apalutamide due to the possibility of significantly decreased plasma concentrations of panobinostat. Apalutamide is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Apomorphine: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or more during therapy; permanently discontinue if QT prolongation does not resolve. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Use caution if panobinostat and aprepitant, fosaprepitant are used concurrently and monitor for an increase in panobinostat-related adverse effects for several days after administration of a multi-day aprepitant regimen. Panobinostat is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of panobinostat. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Avoid concomitant use of aripiprazole and panobinostat, if possible, especially in patients with risk factors for torsade de pointes (TdP). If use is necessary in patients who are receiving both a CYP3A inhibitor plus panobinostat, an aripiprazole dosage reduction may be required. Dosing recommendations vary based on aripiprazole dosage form and CYP3A inhibitor strength. See prescribing information for details. Additionally, monitor for aripiprazole-related adverse effects and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use may increase aripiprazole exposure and risk for QT prolongation and TdP. Aripiprazole is a CYP2D6 and CYP3A substrate, panobinostat is a moderate CYP2D6 inhibitor, and both medications have been associated with QT prolongation.
Arsenic Trioxide: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include arsenic trioxide.
Artemether; Lumefantrine: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include artemether; lumefantrine.
Asenapine: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include asenapine.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Atazanavir; Cobicistat: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Atomoxetine: (Major) The co-administration of panobinostat and atomoxetine is not recommended. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of atomoxetine toxicity. Panobinostat is a CYP2D6 inhibitor and atomoxetine is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Azithromycin: (Major) Concomitant use of panobinostat and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bedaquiline: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include bedaquiline.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, use caution when co-administering moderate inhibitors of CYP2D6 such as panobinostat. The manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. If panobinostat is used in combination with brexpiprazole and a moderate to strong CYP3A4 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Buprenorphine: (Major) Concomitant use of panobinostat and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine; Naloxone: (Major) Concomitant use of panobinostat and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Cabotegravir; Rilpivirine: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Carbamazepine: (Major) Avoid the concomitant use of panobinostat and carbamazepine; panobinostat levels may be significantly decreased and its efficacy reduced. Carbamazepine is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Celecoxib; Tramadol: (Major) Avoid the concomitant use of panobinostat and tramadol as increased tramadol levels and an increased risk of adverse effects may occur if these agents are used together. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tramadol toxicity including seizures and serotonin syndrome. Panobinostat is a CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Ceritinib: (Major) Coadministration of panobinostat and ceritinib is not recommended due to the potential for QT prolongation; increased panobinostat exposure is also possible. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Panobinostat is primarily metabolized by CYP3A4 and is also associated with QT prolongation. Coadministration with a strong CYP3A4 inhibitor increased the Cmax and AUC of panobinostat by 62% and 73%, respectively.
Chlordiazepoxide; Amitriptyline: (Major) The co-administration of panobinostat with tricyclic antidepressants such as amitriptyline is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Chloroquine: (Major) Avoid coadministration of chloroquine with panobinostat due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. QT prolongation has also been reported with panobinostat.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Chlorpheniramine; Dextromethorphan: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with panobinostat may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Panobinostat is a moderate inhibitor of CYP2D6.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with panobinostat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of panobinostat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If panobinostat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Panobinostat is a moderate inhibitor of CYP2D6.
Chlorpromazine: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include chlorpromazine.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Major) Concomitant use of panobinostat and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of panobinostat with cisapride is contraindicated. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride.
Citalopram: (Major) Concomitant use of panobinostat and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) The co-administration of panobinostat with clarithromycin is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Clarithromycin is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. This interaction may be relevant to combination products containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole (Prevpac) and amoxicillin; clarithromycin; omeprazole (Omeclamox-Pak) triple therapy packs.
Clofazimine: (Major) Concomitant use of clofazimine and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Minor) The co-administration of panobinostat with tricyclic antidepressants such as clomipramine is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Clozapine: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include clozapine. In addition, it is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cobicistat: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Codeine: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Codeine; Phenylephrine; Promethazine: (Major) The co-administration of panobinostat with promethazine or promethazine combination products such as meperidine; promethazine and phenylephrine; promethazine is not recommended; QT prolongation has been reported with panobinostat and promethazine. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of promethazine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and promethazine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%). (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Codeine; Promethazine: (Major) The co-administration of panobinostat with promethazine or promethazine combination products such as meperidine; promethazine and phenylephrine; promethazine is not recommended; QT prolongation has been reported with panobinostat and promethazine. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of promethazine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and promethazine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%). (Moderate) Concomitant use of codeine with panobinostat may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of panobinostat could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If panobinostat is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Panobinostat is a moderate inhibitor of CYP2D6.
Crizotinib: (Major) Coadministration of crizotinib with panobinostat is not recommended due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has also been reported with panobinostat.
Daclatasvir: (Major) Systemic exposure of panobinostat, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of panobinostat; monitor patients for potential adverse effects.
Darunavir; Cobicistat: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Dasatinib: (Major) Coadministration of panobinostat and dasatinib is not recommended due to the potential for QT prolongation. QT prolongation has been reported with panobinostat. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Use of panobinostat with degarelix is not recommended due to the risk of QT prolongation. If concomitant use is unavoidable, frequently monitor ECGs for QT prolongation. Prolongation of the QT interval has been reported with panobinostat. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Desflurane: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include halogenated anesthetics.
Desipramine: (Major) The co-administration of panobinostat with tricyclic antidepressants such as desipramine is not recommended; QT prolongation has been reported with these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Deutetrabenazine: (Major) Use of panobinostat with deutetrabenazine is not recommended. QT prolongation has been reported with panobinostat. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dextromethorphan; Bupropion: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dextromethorphan; Guaifenesin: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Dextromethorphan; Quinidine: (Contraindicated) Because of the potential for torsade de pointes, avoid the use of quinidine or dextromethorphan; quinidine with panobinostat. Panobinostat is a CYP2D6 inhibitor and quinidine is a CYP2D6 substrate. When a single 60-mg dose of dextromethorphan was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%). (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Disopyramide: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue i

f QT prolongation does not resolve. Antiarrhythmic medicines with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include disopyramide.
Dofetilide: (Major) Coadministration of dofetilide and panobinostat is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation has been reported with panobinostat.
Dolasetron: (Major) The co-administration of panobinostat with antiemetic agents such as dolasetron may increase the risk of QT prolongation. If concomitant use cannot be avoided, obtain electrocardiograms frequently and closely monitor patients for signs and symptoms of dolasetron toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and dolasetron is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Dolutegravir; Rilpivirine: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Doxepin: (Major) The co-administration of panobinostat with tricyclic antidepressants such as doxepin is not recommended; QT prolongation has been reported with these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Dronedarone: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of panobinostat with dronedarone is contraindicated. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include droperidol.
Efavirenz: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval, such as efavirenz, is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue if QT prolongation does not resolve. In addition, efavirenz may induce the CYP3A4 metabolism of panobinostat, potentially reducing the efficacy of panobinostat by decreasing its systemic exposure.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval, such as efavirenz, is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue if QT prolongation does not resolve. In addition, efavirenz may induce the CYP3A4 metabolism of panobinostat, potentially reducing the efficacy of panobinostat by decreasing its systemic exposure.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval, such as efavirenz, is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue if QT prolongation does not resolve. In addition, efavirenz may induce the CYP3A4 metabolism of panobinostat, potentially reducing the efficacy of panobinostat by decreasing its systemic exposure.
Elbasvir; Grazoprevir: (Major) Administering panobinostat with grazoprevir may result in elevated panobinostat plasma concentrations. Panobinostat is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eliglustat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include eliglustat.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Encorafenib: (Major) Avoid coadministration of encorafenib and panobinostat due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has been reported with panobinostat.
Entrectinib: (Major) Avoid coadministration of entrectinib with panobinostat due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has also been reported with panobinostat.
Enzalutamide: (Major) Avoid the concomitant use of panobinostat and enzalutamide; panobinostat levels may be significantly decreased and its efficacy reduced. Enzalutamide is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was coadministered with panobinostat.
Eribulin: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include eribulin.
Erythromycin: (Major) The co-administration of panobinostat with erythromycin or erythromycin; sulfisoxazole is not recommended; QT prolongation has been reported with panobinostat and erythromycin and the levels of panobinostat may increase. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of erythromycin and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Erythromycin is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
Escitalopram: (Major) Concomitant use of panobinostat and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fingolimod: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include fingolimod.
Flecainide: (Major) The co-administration of panobinostat with flecainide is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of flecainide toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and flecainide is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Fluconazole: (Contraindicated) Because of the potential for QT prolongation and torsade de pointes, the concomitant use of fluconazole and panobinostat is contraindicated. Fluconazole is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial.
Fluoxetine: (Major) The co-administration of panobinostat with fluoxetine is not recommended; QT prolongation has been reported with both agents. Additionally, levels of both drugs may be increased. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of fluoxetine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of fluoxetine and/or panobinostat toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Fluoxetine is a CYP3A4 inhibitor and a CYP2D6 substrate and panobinostat is a CYP3A4 substrate and CYP2D6 inhibitor. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and panobinostat. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. QT prolongation has been reported with panobinostat and concurrent use with other agents that prolong the QT interval is not recommended.
Fosamprenavir: (Major) Concomitant use of panobinostat and fosamprenavir may result in altered panobinostat plasma concentrations. Panobinostat is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a potent inhibitor and moderate inducer of CYP3A4.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as panobinostat. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Obtain an electrocardiogram and electrolyte concentrations at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or more during therapy; permanently discontinue if QT prolongation does not resolve.
Fosphenytoin: (Major) Avoid the concomitant use of panobinostat and phenytoin or fosphenytoin; panobinostat levels may be significantly decreased and its efficacy reduced. Phenytoin and fosphenytoin are strong CYP3A4 inducers and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Fostemsavir: (Major) Use of panobinostat with fostemsavir is not recommended. QT prolongation has been reported with panobinostat. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with panobinostat is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and panobinostat is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Gemifloxacin: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include gemifloxacin.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with panobinostat due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. QT prolongation has been reported with panobinostat.
Gilteritinib: (Major) Coadministration of panobinostat and gilteritinib is not recommended. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Coadministration of glasdegib and panobinostat is not recommended due to the potential for additive QT prolongation. QT prolongation has been reported with panobinostat. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and panobinostat as coadministration may increase serum concentrations of panobinostat and increase the risk of adverse effects. Panobinostat is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and panobinostat as coadministration may increase serum concentrations of panobinostat and increase the risk of adverse effects. Panobinostat is a substrate of P-glycoprotein (P-gp); pibrentasvir is an inhibitor of P-gp.
Goserelin: (Major) Coadministration of panobinostat with goserelin is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat treatment. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include granisetron.
Grapefruit juice: (Major) Avoid taking star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice with panobinostat. These fruits are strong CYP3A4 inhibitors and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with panobinostat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of panobinostat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If panobinostat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Panobinostat is a moderate inhibitor of CYP2D6.
Halogenated Anesthetics: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include halogenated anesthetics.
Haloperidol: (Major) The co-administration of panobinostat with haloperidol is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of haloperidol toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and haloperidol is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Histrelin: (Major) Coadministration of panobinostat with histrelin is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat treatment. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with panobinostat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of panobinostat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If panobinostat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Panobinostat is a moderate inhibitor of CYP2D6.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with panobinostat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of panobinostat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If panobinostat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Panobinostat is a moderate inhibitor of CYP2D6.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with panobinostat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of panobinostat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If panobinostat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Panobinostat is a moderate inhibitor of CYP2D6.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with panobinostat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of panobinostat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If panobinostat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Panobinostat is a moderate inhibitor of CYP2D6.
Hydroxychloroquine: (Major) Concomitant use of panobinostat and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of panobinostat and hydroxyzine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibutilide: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Antiarrhythmic medicines with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include ibutilide.
Iloperidone: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include iloperidone.
Imipramine: (Major) The co-administration of panobinostat with tricyclic antidepressants such as imipramine is not recommended; QT prolongation has been reported with these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Indinavir: (Major) Use caution when administering panobinostat and indinavir together; reduce the initial panobinostat dose from 20 mg PO to 10 mg PO. Indinavir is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with panobinostat due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and panobinostat have been associated with QT interval prolongation.
Isoflurane: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include halogenated anesthetics.
Itraconazole: (Major) Avoid coadministration of itraconazole and panobinostat due to the potential for additive effects on the QT interval; increased exposure to panobinostat may also occur. If these drugs are administered together, reduce the starting dose of panobinostat to 10 mg. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or higher during therapy; permanently discontinue if QT prolongation does not resolve. Coadministration of itraconazole (a potent CYP3A4 inhibitor) with panobinostat (a CYP3A4 substrate) results in elevated panobinostat plasma concentrations and may increase the risk for adverse events, including QT prolongation. The Cmax and AUC of panobinostat were increased by 62% and 73%, respectively, when administered with a strong CYP3A4 inhibitor. In addition, both panobinostat and itraconazole are associated with QT prolongation; coadministration may increase this risk. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with panobinostat due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation has been reported with panobinostat.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and panobinostat due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of panobinostat, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the starting dose of panobinostat to 10 mg. Panobinostat is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of panobinostat by 73%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) The co-administration of panobinostat with clarithromycin is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Clarithromycin is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. This interaction may be relevant to combination products containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole (Prevpac) and amoxicillin; clarithromycin; omeprazole (Omeclamox-Pak) triple therapy packs.
Lapatinib: (Major) Coadministration of panobinostat with lapatinib is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Avoid coadministration of lefamulin with panobinostat as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation has been reported with panobinostat.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with panobinostat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation has also been reported with panobinostat.
Letermovir: (Moderate) An increase in the plasma concentration of panobinostat may occur if given with letermovir. Reduce the starting dose of panobinostat to 10 mg in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Panobinostat is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of panobinostat by 62% and 73%, respectively.
Leuprolide: (Major) Coadministration of panobinostat with leuprolide is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat treatment. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Coadministration of panobinostat with leuprolide is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat treatment. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Levofloxacin: (Major) Concomitant use of panobinostat and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and panobinostat due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of panobinostat, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the starting dose of panobinostat to 10 mg. Panobinostat is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of panobinostat by 73%.
Lithium: (Major) Concomitant use of panobinostat and lithium increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lofexidine: (Major) Coadministration of lofexidine and panobinostat is not recommended due to the potential for additive QT prolongation. Monitor the ECG for QT prolongation if coadministration is required. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Panobinostat can cause QT prolongation.
Lonafarnib: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with lonafarnib. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Loperamide: (Major) Concomitant use of loperamide and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with panobinostat due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with QT prolongation. (Major) Reduce the starting dose of panobinostat to10 mg when coadministered with ritonavir. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of panobinostat by significantly decreasing its systemic exposure; avoid concomitant use. Approximately 40% of the total hepatic panobinostat elimination occurs via CYP3A. Lumacaftor is a strong CYP3A inducer. Simulations using mechanistic models suggest the systemic exposure of panobinostat would decrease approximately 70% if coadministered with a strong CYP3A inducer, such as lumacaftor; ivacaftor. Additionally, panobinostat is a P-glycoprotein (P-gp) substrate and in vitro data suggests lumacaftor; ivacaftor may induce and/or inhibit P-gp transport. Although induction of panobinostat through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as panobinostat. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QT prolongation has been reported with panobinostat.
Maprotiline: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include maprotiline.
Mefloquine: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include mefloquine.
Methadone: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include methadone.
Metoprolol: (Major) The co-administration of panobinostat and metoprolol is not recommended. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of metoprolol toxicity. Panobinostat is a CYP2D6 inhibitor and metoprolol is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) The co-administration of panobinostat and metoprolol is not recommended. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of metoprolol toxicity. Panobinostat is a CYP2D6 inhibitor and metoprolol is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Metronidazole: (Major) Concomitant use of metronidazole and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mexiletine: (Major) The co-administration of panobinostat with mexiletine is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of mexiletine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and mexiletine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Midostaurin: (Major) Avoid the concomitant use of midostaurin and panobinostat; both drugs have been reported to increase the QT interval. Obtain an electrocardiogram at baseline and periodically during panobinostat treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue if QT prolongation does not resolve. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial.
Mifepristone: (Major) The co-administration of panobinostat with mifepristone is not recommended; QT prolongation has been reported with both agents. Mifepristone is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of mifepristone and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Mirtazapine: (Major) Concomitant use of panobinostat and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitotane: (Major) Avoid the concomitant use of mitotane with panobinostat due to decreased exposure and possible decreased efficacy. Mitotane is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of panobinostat. 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.
Mobocertinib: (Major) Concomitant use of mobocertinib and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Nebivolol: (Major) Avoid the concomitant use of nebivolol and panobinostat. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of nebivolol toxicity. Panobinostat is a CYP2D6 inhibitor and nebivolol is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and panobinostat. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of nebivolol toxicity. Panobinostat is a CYP2D6 inhibitor and nebivolol is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Nefazodone: (Major) Use caution when administering panobinostat and nefazodone together; reduce the initial panobinostat dose from 20 mg PO to 10 mg PO. Nefazodone is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
Nelfinavir: (Major) Use caution when administering panobinostat and nelfinavir together; reduce the initial panobinostat dose from 20 mg PO to 10 mg PO. Nelfinavir is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
Nilotinib: (Major) The co-administration of panobinostat with nilotinib is not recommended; QT prolongation has been reported with both agents. Nilotinib is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of nilotinib and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Nirmatrelvir; Ritonavir: (Major) Reduce the starting dose of panobinostat to10 mg when coadministered with ritonavir. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Nortriptyline: (Major) The co-administration of panobinostat with tricyclic antidepressants such as nortriptyline is not recommended; QT prolongation has been reported with these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Ofloxacin: (Major) Concomitant use of panobinostat and ofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) The co-administration of panobinostat with olanzapine is not recommended; QT prolongation has been reported with both drugs. Additionally, levels of olanzapine may be increased. If concomitant use of olanzapine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of olanzapine toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Olanzapine is a CYP2D6 substrate, and panobinostat is a CYP2D6 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Olanzapine; Fluoxetine: (Major) The co-administration of panobinostat with fluoxetine is not recommended; QT prolongation has been reported with both agents. Additionally, levels of both drugs may be increased. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of fluoxetine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of fluoxetine and/or panobinostat toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Fluoxetine is a CYP3A4 inhibitor and a CYP2D6 substrate and panobinostat is a CYP3A4 substrate and CYP2D6 inhibitor. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%). (Major) The co-administration of panobinostat with olanzapine is not recommended; QT prolongation has been reported with both drugs. Additionally, levels of olanzapine may be increased. If concomitant use of olanzapine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of olanzapine toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Olanzapine is a CYP2D6 substrate, and panobinostat is a CYP2D6 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Olanzapine; Samidorphan: (Major) The co-administration of panobinostat with olanzapine is not recommended; QT prolongation has been reported with both drugs. Additionally, levels of olanzapine may be increased. If concomitant use of olanzapine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of olanzapine toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Olanzapine is a CYP2D6 substrate, and panobinostat is a CYP2D6 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and panobinostat is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and panobinostat may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If panobinostat is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and panobinostat is a moderate CYP2D6 inhibitor.
Ondansetron: (Major) The co-administration of panobinostat with antiemetic agents such as ondansetron may increase the risk of QT prolongation. If concomitant use cannot be avoided, obtain electrocardiograms frequently and closely monitor patients for signs and symptoms of ondansetron toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and ondansetron is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Osilodrostat: (Major) Coadministration of osilodrostat and panobinostat is not recommended due to the potential for additive QT prolongation. Panobinostat can cause QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) According to the manufacturer of panobinostat, coadministration with other agents that prolong the QT interval, such as osimertinib, is not recommended. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, and QT prolongation has also been reported with panobinostat. Additionally, panobinostat is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor; concomitant use may increase panobinostat exposure.
Oxaliplatin: (Major) Concomitant use of panobinostat with oxaliplatin is not recommended due to the risk of QT prolongation. QT prolongation has been reported with panobinostat; QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking panobinostat due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QT prolongation has been reported with panobinostat.
Pacritinib: (Major) Concomitant use of pacritinib and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. If coadministration is required, obtain an electrocardiogram (ECG) at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or more during therapy; permanently discontinue if QT prolongation does not resolve. Closely monitor patients with known risk factors for cardiac disease or arrhythmias.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with panobinostat is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and panobinostat is a moderate CYP2D6 inhibitor.
Pasireotide: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include pasireotide.
Pazopanib: (Major) The co-administration of panobinostat with pazopanib is not recommended; QT prolongation has been reported with both agents. Pazopanib is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of pazopanib and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Pentamidine: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include pentamidine.
Perphenazine: (Major) The co-administration of panobinostat and perphenazine is not recommended. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of perphenazine toxicity. Panobinostat is a CYP2D6 inhibitor and perphenazine is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Perphenazine; Amitriptyline: (Major) The co-administration of panobinostat and perphenazine is not recommended. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of perphenazine toxicity. Panobinostat is a CYP2D6 inhibitor and perphenazine is a CYP2D6-sensitive substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%). (Major) The co-administration of panobinostat with tricyclic antidepressants such as amitriptyline is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Phenobarbital: (Major) Avoid the concomitant use of panobinostat and phenobarbital or phenobarbital combination products such as atropine; hyoscyamine; phenobarbital; scopolamine and belladonna alkaloids; ergotamine; phenobarbital; panobinostat levels may be significantly decreased and its efficacy reduced. Phenobarbital is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of panobinostat and phenobarbital or phenobarbital combination products such as atropine; hyoscyamine; phenobarbital; scopolamine and belladonna alkaloids; ergotamine; phenobarbital; panobinostat levels may be significantly decreased and its efficacy reduced. Phenobarbital is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Phenytoin: (Major) Avoid the concomitant use of panobinostat and phenytoin or fosphenytoin; panobinostat levels may be significantly decreased and its efficacy reduced. Phenytoin and fosphenytoin are strong CYP3A4 inducers and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Pimavanserin: (Major) Coadministration of pimavanserin and panobinostat is not recommended. Pimavanserin may cause QT prolongation. QT prolongation has also been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. If coadministration cannot be avoided, obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Pimozide: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of pimozide with panobinostat is contraindicated. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Pimozide is associated with a well-established risk of QT prolongation and TdP.
Pitolisant: (Major) Avoid coadministration of pitolisant with panobinostat as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QT prolongation has been reported with panobinostat.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking panobinostat due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QT prolongation has been reported with panobinostat.
Posaconazole: (Contraindicated) Because of the potential for QT prolongation and torsade de pointes, avoid the concomitant use of ketoconazole, itraconazole, posaconazole, or voriconazole with panobinostat. These agents are strong CYP3A4 inhibitors and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in 14 patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking ketoconazole 200 mg PO twice daily for 14 days.
Primidone: (Major) Avoid the concomitant use of panobinostat and primidone; panobinostat levels may be significantly decreased and its efficacy reduced. Primidone is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Procainamide: (Major) The co-administration of panobinostat with procainamide is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of procainamide toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and procainamide is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Promethazine: (Major) The co-administration of panobinostat with promethazine or promethazine combination products such as meperidine; promethazine and phenylephrine; promethazine is not recommended; QT prolongation has been reported with panobinostat and promethazine. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of promethazine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and promethazine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Promethazine; Dextromethorphan: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied. (Major) The co-administration of panobinostat with promethazine or promethazine combination products such as meperidine; promethazine and phenylephrine; promethazine is not recommended; QT prolongation has been reported with panobinostat and promethazine. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of promethazine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and promethazine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Promethazine; Phenylephrine: (Major) The co-administration of panobinostat with promethazine or promethazine combination products such as meperidine; promethazine and phenylephrine; promethazine is not recommended; QT prolongation has been reported with panobinostat and promethazine. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of promethazine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and promethazine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Propafenone: (Major) The co-administration of panobinostat with propafenone is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of propafenone toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and propafenone is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Protriptyline: (Minor) The co-administration of panobinostat with tricyclic antidepressants such as prortriptyline should be approached with caution; QT prolongation has been reported with these agents. If administered together, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Quetiapine: (Major) Concomitant use of quetiapine and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Contraindicated) Because of the potential for torsade de pointes, avoid the use of quinidine or dextromethorphan; quinidine with panobinostat. Panobinostat is a CYP2D6 inhibitor and quinidine is a CYP2D6 substrate. When a single 60-mg dose of dextromethorphan was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Quinine: (Major) The co-administration of panobinostat with quinine is not recommended; QT prolongation has been reported with both agents. Quinine is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of quinine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Quizartinib: (Major) Concomitant use of quizartinib and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) The co-administration of panobinostat with ranolazine is not recommended; QT prolongation has been reported with both agents. Ranolazine is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of ranolazine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Relugolix: (Major) Use of panobinostat with relugolix is not recommended. QT prolongation has been reported with panobinostat. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Use of panobinostat with relugolix is not recommended. QT prolongation has been reported with panobinostat. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Ribociclib: (Major) Avoid coadministration of ribociclib with panobinostat due to an increased risk for QT prolongation. Systemic exposure of panobinostat may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Panobinostat is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with panobinostat due to an increased risk for QT prolongation. Systemic exposure of panobinostat may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Panobinostat is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
Rifapentine: (Major) Avoid the concomitant use of panobinostat and rifapentine due to the possibility of significantly decreased plasma concentrations of panobinostat. Rifapentine is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Rilpivirine: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Risperidone: (Major) The coadministration of panobinostat with risperidone should be avoided if possible; both agents have a possible risk for QT prolongation and torsade de pointes. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is recommended.
Ritonavir: (Major) Reduce the starting dose of panobinostat to10 mg when coadministered with ritonavir. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Romidepsin: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include romidepsin.
Saquinavir: (Major) The co-administration of panobinostat with saquinavir is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Saquinavir is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Selpercatinib: (Major) Coadministration of selpercatinib and panobinostat is not recommended due to the potential for additive QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. QT prolongation has been reported with panobinostat.
Sertraline: (Major) Concomitant use of sertraline and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include halogenated anesthetics.
Siponimod: (Major) Avoid coadministration of siponimod and panobinostat due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation has been reported with panobinostat.
Sodium Phenylbutyrate: (Major) Avoid coadministration of sodium phenylbutyrate and panobinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and panobinostat are inhibitors of histone deacetylase (HDAC).
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate and panobinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and panobinostat are inhibitors of histone deacetylase (HDAC).
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of panobinostat, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
Solifenacin: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include solifenacin.
Sorafenib: (Major) Use of panobinostat with sorafenib is not recommended due to the risk of additive QT prolongation. QT prolongation has been reported with panobinostat. Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Concomitant use of sotalol and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of panobinostat and St. John's Wort; panobinostat levels may be significantly decreased and its efficacy reduced. St. John's Wort is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Sunitinib: (Major) Concomitant use of panobinostat with other agents that prolong the QT interval, such as sunitinib, is not recommended. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Prolongation of the QT interval has also been reported with panobinostat.
Tacrolimus: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include tacrolimus.
Telavancin: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include telavancin.
Tetrabenazine: (Major) The co-administration of panobinostat with tetrabenazine is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tetrabenazine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tetrabenazine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Thioridazine: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of thioridazine with panobinostat is contraindicated. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Thioridazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP and is contraindicated for use with other drugs that are known to prolong the QT interval.
Tolterodine: (Major) The co-administration of panobinostat with tolterodine is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tolterodine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tolterodine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Toremifene: (Major) Coadministration of panobinostat with toremifene is not recommended due to the risk of additive QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval has also been reported with panobinostat.
Tramadol: (Major) Avoid the concomitant use of panobinostat and tramadol as increased tramadol levels and an increased risk of adverse effects may occur if these agents are used together. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tramadol toxicity including seizures and serotonin syndrome. Panobinostat is a CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Tramadol; Acetaminophen: (Major) Avoid the concomitant use of panobinostat and tramadol as increased tramadol levels and an increased risk of adverse effects may occur if these agents are used together. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tramadol toxicity including seizures and serotonin syndrome. Panobinostat is a CYP2D6 inhibitor and tramadol is primarily metabolized by CYP2D6. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Trazodone: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include trazodone.
Triclabendazole: (Major) Concomitant use of triclabendazole and panobinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trimipramine: (Major) The co-administration of panobinostat with tricyclic antidepressants such as trimipramine is not recommended; QT prolongation has been reported with these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Triptorelin: (Major) Coadministration of panobinostat with triptorelin is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat treatment. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Tucatinib: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with tucatinib. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Vandetanib: (Major) Coadministration of vandetanib with panobinostat is not recommended due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Prolongation QT prolongation has also been reported with panobinostat.
Vardenafil: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include vardenafil.
Vemurafenib: (Major) The co-administration of panobinostat with vemurafenib is not recommended; QT prolongation has been reported with both agents. Additionally, vemurafenib is a CYP3A4 inducer and panobinostat is a CYP3A4 substrate; panobinostat levels may be significantly decreased and its efficacy reduced. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Venlafaxine: (Major) The co-administration of panobinostat with venlafaxine is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of venlafaxine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and venlafaxine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Voclosporin: (Major) Avoid concomitant use of panobinostat with voclosporin due to the risk of additive QT prolongation. QT prolongation has been reported with panobinostat. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) The co-administration of panobinostat with clarithromycin is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Clarithromycin is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. This interaction may be relevant to combination products containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole (Prevpac) and amoxicillin; clarithromycin; omeprazole (Omeclamox-Pak) triple therapy packs.
Voriconazole: (Major) Avoid coadministration of voriconazole and panobinostat due to the potential for additive effects on the QT interval; increased exposure to panobinostat may also occur. If these drugs are administered together, reduce the starting dose of panobinostat to 10 mg. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or higher during therapy; permanently discontinue if QT prolongation does not resolve. Coadministration of voriconazole (a strong CYP3A4 inhibitor) with panobinostat (a CYP3A4 substrate) results in elevated panobinostat plasma concentrations and may increase the risk for adverse events, including QT prolongation. The Cmax and AUC of panobinostat were increased by 62% and 73%, respectively, when administered with a strong CYP3A4 inhibitor. In addition, both panobinostat and voriconazole are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include vorinostat.
Ziprasidone: (Contraindicated) Coadministration of panobinostat and ziprasidone is contraindicated since there is an increased risk for QT prolongation and torsade de pointes (TdP). Ziprasidone is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including panobinostat. Severe arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving panobinostat therapy. Concomitant use of other drugs that are known to prolong the QT interval is not recommended with panobinostat.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and panobinostat is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

FARYDAK/Panobinostat Oral Cap: 10mg, 15mg, 20mg

Adults

20 mg/dose PO; 10 mg/dose PO if taking a strong CYP3A4 inhibitor.

Geriatric

20 mg/dose PO; 10 mg/dose PO if taking a strong CYP3A4 inhibitor.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Panobinostat is a pan-histone deacetylase (HDAC)-inhibitor that works by blocking the enzymatic activity of HDAC causing hyperacetylation of histone proteins leading to many cellular effects including cell cycle arrest, apoptosis (caspase-dependent and independent) apoptosis, and inhibition of angiogenesis. It belongs to a novel class of cynnamic acid hydroxamates that act on cells at nanomolar concentrations. The HDAC enzymes are overexpressed in several cancers, including multiple myeloma as well as tumor cells derived from multiple myeloma patients known to be refractory to doxorubicin, mitoxantrone, melphalan, dexamethasone, and bortezomib. The activity of panobinostat in bortezomib-resistant cells and the synergy with bortezomib may be attributed to alpha-tubulin hyperacetylation and a reduction in bortezomib-induced aggresome formation.

Panobinostat is administered orally. It is approximately 90% protein bound in vitro and is not concentration dependent. Panobinostat is metabolized through metabolic pathways involving reduction, hydrolysis, oxidation, and glucuronidation. Following a single oral dose of [14C]-panobinostat administered to 4 patients with advanced cancer, 29% to 51% of the radioactivity was excreted in the urine and 44% to 77% of the radioactivity was excreted in the feces. A small amount of unchanged drug was found in the urine (< 2.5%) and feces (< 3.5%). In a population pharmacokinetic analysis, the estimated oral clearance (CL/F) was 160 L/hour (intersubject variability, 65%) and the estimated terminal elimination half-life was 37 hours in patients with advanced cancer.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2D6
Panobinostat is a CYP3A4 substrate and CYP3A accounts for approximately 40% of the total hepatic panobinostat elimination. In vitro, metabolism is minor via CYP2D6 and CYP2C19 isoenzymes. Avoid the concomitant use of panobinostat with strong CYP3A4 inducers and sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic index. A dose adjustment is recommended when panobinostat is co-administered with strong CYP3A4 inhibitors. A significant interaction is unlikely with other CYP3A substrates. Using a physiologically-based pharmacokinetic model, exposure was increased by less than 10% when a sensitive CYP3A substrate, midazolam, was co-administered with panobinostat. Panobinostat glucuronidation occurs via UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B4 in vitro. Panobinostat is also a P-glycoprotein substrate. Panobinostat inhibits OAT3, OCT1, OCT2, OATP1B1 and OATP1B3 and has demonstrated time-dependent inhibition of CYP2D6, CYP2C19 and CYP3A4 in in vitro studies.

Oral Route

The absolute oral bioavailability of panobinostat is about 21%. It exhibits a proportional dose increase in Cmax and AUC values over the dosing range. The Tmax occurs within 2 hours of oral administration. In patients with advanced cancer, chronic oral dosing of panobinostat resulted in up to a 2-fold accumulation of drug. The aqueous solubility of panobinostat is pH dependent, with a higher pH resulting in lower solubility; however, coadministration with drugs that elevate the gastric pH has not been studied and physiologically-based pharmacokinetic models predict unaltered panobinostat absorption.
 
Affects of food: Compared with fasting conditions, the Cmax and AUC(0-48 hr) were about 44% and 16% lower, respectively, when panobinostat was administered 30 minutes after a high-fat meal in 36 patients with advanced cancer. Additionally, the median Tmax was delayed by 2.5 hours in these patients. Panobinostat should be taken at about the same time every day with or without food.

Pregnancy

Panobinostat may cause fetal harm when administered to a pregnant woman, based on animal data. Advise females of reproductive potential to avoid becoming pregnant while taking panobinostat. Discuss the potential hazard to the fetus if panobinostat is used during pregnancy or if a patient becomes pregnant while taking this drug. In pregnant rats, embryofetal toxicities including cleft palate, short tail, extra presacral vertebrae, and extra ribs occurred at doses that resulted in AUC values about 3-times the human exposure at the human dose of 20 mg. In pregnant rabbits, embryofetal malformations such as absent digits, cardiac interventricular septal defects, aortic arch interruption, missing gallbladder, and irregular ossification of skull occurred at doses that resulted in AUC values about 7-times the human exposure at the human dose of 20 mg.

Pregnancy testing should be performed in women of childbearing potential prior to starting and periodically during panobinostat therapy. Discuss contraception requirements with both male and female patients due to the potential for reproductive risk with panobinostat. Sexually-active females of reproductive potential should be advised to use effective contraception while taking panobinostat and for at least 3 months after the last dose. Women who become pregnant or suspect a pregnancy should contact their healthcare provider. Because of the potential risk of male-mediated teratogenicity, sexually active men who are receiving panobinostat should be advised to use condoms while on treatment and for at least 6 months after their last dose. Panobinostat may cause male and female infertility, based on animal studies. An increase in early resorption and/or post-implantation loss in female rats occurred with panobinostat doses 10 mg/kg or greater (given 3 times weekly on days 1, 3, and 5 for 2 weeks prior to mating). Prostate atrophy with reduced secretory granules, testicular degeneration, oligospermia, and increased epididymal debris were observed following repeated oral doses of 1.5 mg/kg over a 4-week study period in dogs; effects were not completely reversed following a 4-week nondosing period.