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    Histone Deacetylase Inhibitors

    BOXED WARNING

    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, cardiac arrhythmias, long QT syndrome, myocardial infarction, QT prolongation

    Severe ischemic events, cardiac arrhythmias, and electrocardiogram (ECG) changes have 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), 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 during therapy; permanently discontinue therapy if the QT prolongation does not resolve.

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Histone deacetylase inhibitor
    Indicated in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent
    Severe and fatal cardiac ischemic events, severe arrhythmias, have occurred; obtain an ECG and electrolytes at baseline and periodically during treatment as clinically indicated

    COMMON BRAND NAMES

    FARYDAK

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    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.
    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

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    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.

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual precautions for handling, preparing, and administering cytotoxic drugs.

    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.

    STORAGE

    FARYDAK:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    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, cardiac arrhythmias, long QT syndrome, myocardial infarction, QT prolongation

    Severe ischemic events, cardiac arrhythmias, and electrocardiogram (ECG) changes have 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), 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 during therapy; permanently discontinue therapy if the QT prolongation does not resolve.

    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.

    Anemia, bleeding, GI bleeding, neutropenia, pulmonary bleeding, thrombocytopenia

    Severe myelosuppression (e.g., anemia, neutropenia, and thrombocytopenia) and bleeding (e.g., pulmonary bleeding and GI bleeding) have occurred in patients who received panobinostat; fatal hemorrhagic events in patients with severe grade 3 or higher thrombocytopenia were reported in a clinical trial. Some patients required platelet transfusions. Monitor complete blood counts with differential prior to and at least weekly during treatment; also monitor platelet counts and transfuse as needed. Before starting panobinostat therapy, the baseline platelet count should be 100 x 109 cells/L or greater and the absolute neutrophil count should be 1.5 x 109 cells/L or greater. Therapy interruption, a dose adjustment, and/or drug discontinuation may be necessary if severe toxicity occurs during therapy.

    Fungal infection, infection, viral infection

    Infection (e.g., pneumonia, bacterial infection, invasive fungal infection, and viral infection) has occurred in patients who received panobinostat, some cases were fatal. Do not start panobinostat in patients who have an active infection. Monitor patients for signs and symptoms of infection. Promptly treat with anti-infective agents and consider therapy interruption or discontinuation in patients who develop an infection.

    Hepatic disease

    Hepatotoxicity (e.g., elevated aminotransferase levels, hyperbilirubinemia) has occurred in patients who received panobinostat. An initial dose adjustment is recommended in patients with mild or moderate hepatic disease; avoid use in patients with severe hepatic disease. Monitor liver function tests (LFTs) prior to and regularly during treatment. A panobinostat dose reduction or therapy interruption may be necessary in patients who develop severe or recurrent hepatotoxicity; follow LFTs until toxicity resolution or values return to baseline.

    Children, infants, neonates

    The safety and efficacy of panobinostat have not been established in adolescents, children, infants, or neonates.

    Geriatric

    Patients aged greater than 65 years experienced more toxicity (e.g., gastrointestinal toxicity, myelosuppression, and cardiac toxicity) with panobinostat compared with patients aged 65 years or younger. Additionally, death not related to disease progression occurred in 9% of patients aged 65 years or older compared with 5% of patients younger than 65 years of age. Frequently monitor geriatric patients for signs and symptoms of toxicity.

    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.

    Breast-feeding

    According to the manufacturer, it is not known whether panobinostat is secreted in human milk in a woman who is breast-feeding. Because of the potential of serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding or discontinue panobinostat. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    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.

    ADVERSE REACTIONS

    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
    respiratory arrest / Rapid / 0-12.0
    cardiac arrest / Early / 0-12.0
    atrial tachycardia / Early / 0-12.0
    ventricular tachycardia / Early / 0-12.0
    atrial fibrillation / 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
    GI bleeding / Delayed / Incidence not known

    Moderate

    hyperphosphatemia / Delayed / 27.0-27.0
    sinus tachycardia / Rapid / 0-12.0
    QT prolongation / Rapid / 0-12.0
    palpitations / Early / 0-10.0
    hypertension / Early / 0-10.0
    hypotension / Rapid / 0-10.0
    orthostatic hypotension / Delayed / 0-10.0
    gastritis / Delayed / 0-10.0
    colitis / Delayed / 0-10.0
    dehydration / 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

    dyspepsia / Early / 0-10.0
    xerostomia / Early / 0-10.0
    cheilitis / Delayed / 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 (unspecified) / Early / 0-10.0
    chills / Rapid / 0-10.0
    cough / Delayed / 0-10.0

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Acetaminophen; Dextromethorphan: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Acetaminophen; 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%).
    Albuterol: (Minor) 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 beta-agonists.
    Albuterol; Ipratropium: (Minor) 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 beta-agonists.
    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) 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 amiodarone.
    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%).
    Amitriptyline; Chlordiazepoxide: (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; Lansoprazole: (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.
    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.
    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 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 apomorphine.
    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.
    Arformoterol: (Moderate) 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 beta-agonists.
    Aripiprazole: (Major) The co-administration of panobinostat with aripiprazole 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 aripiprazole toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and aripiprazole is a partial 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%). If aripiprazole and panobinostat are coadministered, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP2D6 inhibitor.
    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.
    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%).
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Azithromycin: (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 azithromycin.
    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.
    Belladonna Alkaloids; Ergotamine; 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.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) The co-administration of panobinostat with metronidazole or metronidazole combination products is not recommended; QT prolongation has been reported with panobinostat and metronidazole. 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.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) The co-administration of panobinostat with metronidazole or metronidazole combination products is not recommended; QT prolongation has been reported with panobinostat and metronidazole. 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.
    Boceprevir: (Major) Use caution when administering panobinostat and boceprevir together; reduce the initial panobinostat dose from 20 mg PO to 10 mg PO. Boceprevir 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.
    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.
    Brigatinib: (Moderate) Monitor for decreased efficacy of panobinostat if coadministration with brigatinib is necessary. Panobinostat is a CYP3A substrate and brigatinib induces CYP3A in vitro. Although not evaluated in vitro or in clinical trials, an approximately 70% decrease in the systemic exposure of panobinostat was observed in the presence of strong CYP3A inducers in simulations using mechanistic models; brigatinib may decrease panobinostat exposure.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Budesonide; Formoterol: (Moderate) 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 beta-agonists.
    Buprenorphine: (Major) Buprenorphine should be avoided in combination with panobinostat. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). According to the manufacturer of panobinostat, use with other agents that prolong the QT interval is not recommended. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. 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.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be avoided in combination with panobinostat. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). According to the manufacturer of panobinostat, use with other agents that prolong the QT interval is not recommended. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. 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.
    Cabozantinib: (Moderate) Monitor for an increase in panobinostat-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of panobinostat may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and panobinostat is a substrate of P-gp; the clinical relevance of this finding is unknown.
    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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Ceritinib: (Major) Coadministration of panobinostat and ceritinib is not recommended due to the potential for QT prolongation; increased panobinostat exposure is also possible. If coadministration cannot be avoided, conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes; monitor for panobinostat adverse effects. Ceritinib is a 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.
    Chloroquine: (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 chloroquine.
    Chlorpheniramine; Dextromethorphan: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    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.
    Ciprofloxacin: (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 ciprofloxacin.
    Cisapride: (Severe) 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) 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 citalopram.
    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.
    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.
    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%).
    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%).
    Conivaptan: (Major) Avoid coadministration of conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and panobinostat, a CYPA4/P-gp substrate. Exposure to panobinostat may increase when the drugs are used together. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. According to the manufacturer of panobinostat, if panobinostat is administered with a strong CYP3A4 inhibitor the initial dose of panobinostat should be reduced from 20 mg PO to 10 mg PO. 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.
    Crizotinib: (Major) Avoid coadministration of panobinostat with crizotinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for both drugs if QT prolongation occurs. Prolongation of the QT interval has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Cyclobenzaprine: (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 cyclobenzaprine.
    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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) The co-administration of panobinostat with ritonavir or lopinavir; ritonavir is not recommended; QT prolongation has been reported with 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. Ritonavir and lopinavir/ritonavir 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.
    Dasatinib: (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 dasatinib.
    Degarelix: (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 degarelix.
    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) Coadministration of deutetrabenazine with panobinostat is not recommended. Clinically relevant QTc prolongation may occur with deutetrabenazine. QT prolongation has been reported with panobinostat therapy.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Dextromethorphan: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Dextromethorphan; Guaifenesin: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    Dextromethorphan; Promethazine: (Major) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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) 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%).
    Dextromethorphan; Quinidine: (Severe) 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) The co-administration of panobinostat and dexchlorpheniramine; dextromethorphan; phenylephrine; pyrilamine and dexchlorpheniramine; dextromethorphan; pseudoephedrine is not recommended is not recommended; levels of dextromethorphan may increase. If concomitant use cannot be avoided, closely monitor for signs and symptoms of dextromethorphan toxicity. Panobinostat is a CYP2D6 inhibitor and dextromethorphan and chlorpheniramine are CYP2D6-sensitive substrates. 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%).
    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 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 disopyramide.
    Dofetilide: (Severe) Because of the potential for torsade de pointes (TdP), use of panobinostat with dofetilide 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. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    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: (Severe) 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: (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.
    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.
    Enflurane: (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.
    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 co-administered 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.
    Erythromycin; Sulfisoxazole: (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) 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 escitalopram.
    Ezogabine: (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 ezogabine.
    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: (Severe) 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%).
    Fluoxetine; Olanzapine: (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%).
    Fluticasone; Salmeterol: (Moderate) 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 beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) 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 beta-agonists.
    Fluticasone; Vilanterol: (Moderate) 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 beta-agonists.
    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.
    Formoterol: (Moderate) 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 beta-agonists.
    Formoterol; Mometasone: (Moderate) 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 beta-agonists.
    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.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and panobinostat are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; panobinostat is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
    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.
    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.
    Glycopyrrolate; Formoterol: (Moderate) 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 beta-agonists.
    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.
    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%).
    Halothane: (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.
    Hydrochlorothiazide, HCTZ; 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%).
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and panobinostat. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. QT prolongation has 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.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include panobinostat.
    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%).
    Indacaterol: (Moderate) 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 beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) 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 beta-agonists.
    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.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole and panobinostat due to the potential for QT prolongation; 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. Both panobinostat and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (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 (0-48hr) of panobinostat 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.
    Lapatinib: (Major) The co-administration of panobinostat with lapatinib is not recommended; QT prolongation has been reported with both agents. Lapatinib 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 lapatinib 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.
    Lenvatinib: (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 lenvatinib.
    Leuprolide: (Moderate) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include panobinostat. The co-administration of panobinostat with leuprolide is not recommended; QT prolongation has been reported with both agents.
    Leuprolide; Norethindrone: (Moderate) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include panobinostat. The co-administration of panobinostat with leuprolide is not recommended; QT prolongation has been reported with both agents.
    Levalbuterol: (Minor) 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 beta-agonists.
    Levofloxacin: (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 levofloxacin.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with panobinostat. Lithium has been associated with QT prolongation.
    Long-acting beta-agonists: (Moderate) 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 beta-agonists.
    Loperamide: (Major) Loperamide should be avoided in combination with panobinostat. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. 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 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. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with panobinostat, a potent CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Loperamide should be avoided in combination with panobinostat. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. 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 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. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with panobinostat, a potent CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) The co-administration of panobinostat with ritonavir or lopinavir; ritonavir is not recommended; QT prolongation has been reported with 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. Ritonavir and lopinavir/ritonavir 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.
    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.
    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.
    Meperidine; 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%).
    Metaproterenol: (Minor) 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 beta-agonists.
    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%).
    Metronidazole: (Major) The co-administration of panobinostat with metronidazole or metronidazole combination products is not recommended; QT prolongation has been reported with panobinostat and metronidazole. 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.
    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, RU-486: (Major) The co-administration of panobinostat with mifepristone, RU-486 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) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and panobinostat. QT prolongation has been reported with panobinostat and concurrent use with other agents that prolong the QT interval is not recommended. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    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.
    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.
    Norfloxacin: (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 norfloxacin.
    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%).
    Octreotide: (Major) The co-administration of panobinostat with octreotide is not recommended; QT prolongation has been reported with both agents. Octreotide 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 octreotide 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.
    Ofloxacin: (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 ofloxacin.
    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%).
    Olodaterol: (Moderate) 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 beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The co-administration of panobinostat with ritonavir or lopinavir; ritonavir is not recommended; QT prolongation has been reported with 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. Ritonavir and lopinavir/ritonavir 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.
    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%).
    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.
    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.
    Paliperidone: (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 paliperidone.
    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.
    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%).
    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: (Severe) 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.
    Pirbuterol: (Minor) 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 beta-agonists.
    Posaconazole: (Severe) 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%).
    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) 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 quetiapine.
    Quinidine: (Severe) 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.
    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.
    Regadenoson: (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 regadenoson.
    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 has been shown to prolong the QT interval in a concentration-dependent manner; QT prolongation has also been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate.
    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 has been shown to prolong the QT interval in a concentration-dependent manner; QT prolongation has also been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate.
    Rifabutin: (Major) Avoid the concomitant use of panobinostat and rifabutin; panobinostat levels may be significantly decreased and its efficacy reduced. Rifabutin 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.
    Rifapentine: (Major) Avoid the concomitant use of panobinostat and rifapentine; panobinostat levels may be significantly decreased and its efficacy reduced. 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) The co-administration of panobinostat with ritonavir or lopinavir; ritonavir is not recommended; QT prolongation has been reported with 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. Ritonavir and lopinavir/ritonavir 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.
    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.
    Salmeterol: (Moderate) 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 beta-agonists.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and panobinostat as coadministration may result in increased systemic exposure of panobinostat. Panobinostat is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of panobinostat.
    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.
    Sertraline: (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 sertraline.
    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.
    Short-acting beta-agonists: (Minor) 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 beta-agonists.
    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) The coadministration of panobinostat with sorafenib is not recommended; QT prolongation has been reported with both agents. If concomitant use of sorafenib 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.
    Sotalol: (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 sotalol.
    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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (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 sulfamethoxazole; trimethoprim, SMX-TMP, Cotrimoxazole.
    Sunitinib: (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. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include sunitinib.
    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.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with panobinostat due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is necessary, obtain an electrocardiogram at baseline and periodically during treatment; additionally, monitor for altered tamoxifen efficacy and/or increased tamoxifen-related adverse effects. Hold panobinostat if the QTcF increases to 480 milliseconds or more during therapy; permanently discontinue if QT prolongation does not resolve. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Panobinostat may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Telaprevir: (Major) Use caution when administering panobinostat and telaprevir together; reduce the initial panobinostat dose from 20 mg PO to 10 mg PO. Telaprevir 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.
    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.
    Telithromycin: (Major) The co-administration of panobinostat with telithromycin 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. Telithromycin 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.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and panobinostat is necessary, as the systemic exposure of panobinostat may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of panobinostat. Panobinostat is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with panobinostat is necessary, and monitor for an increase in panobinostat-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro. Panobinostat is primarily (40%) a CYP3A4 substrate, but is also metabolized by P-gp. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to panobinostat may increase.
    Terbutaline: (Minor) 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 beta-agonists.
    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: (Severe) 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.
    Tiotropium; Olodaterol: (Moderate) 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 beta-agonists.
    Tizanidine: (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 tizanidine.
    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) 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 toremifene.
    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%).
    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.
    Trimethoprim: (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 sulfamethoxazole; trimethoprim, SMX-TMP, Cotrimoxazole.
    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%).
    Umeclidinium; Vilanterol: (Moderate) 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 beta-agonists.
    Vandetanib: (Major) The manufacturers of vandetanib and panobinostat recommend avoiding coadministration with other drugs that prolong the QT interval if possible due to an increased risk of QT prolongation and torsade de pointes (TdP); additionally, an increase in panobinostat-related adverse reactions is possible if these drugs are coadministered. Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib; panobinostat also has a possible risk for QT prolongation. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then vandetanib may be resumed at a reduced dose. Similarly, withhold panobinostat therapy if the QTcF is > 480 msec and permanently discontinue therapy if the at QT prolongation does not resolve. Additionally, panobinostat a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of another P-gp substrate by 29% and 23%, respectively.
    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%).
    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 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: (Severe) Because of the potential for torsade de pointes (TdP), use of ziprasidone 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. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes. 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.
    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.

    PREGNANCY AND LACTATION

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.