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panobinostat

General

**REMS Drug**

Pronunciation:
pan-oh-bin-oh-stat


Trade Name(s)

  • Farydak

Ther. Class.
antineoplastics

Pharm. Class.
enzyme inhibitors

Indications

Treatment of multiple myeloma (with bortezomib and dexamethasone) that has not responded to two previous treatments including bortezomib and an immunomodulator.

Action

Acts as an inhibitor of the enzyme histone deacetylase (HDAC), resulting in cell cycle arrest/apoptosis; cytotoxicity is enhanced in tumor cells.

Therapeutic Effect(s):

Decreased progression of multiple myeloma.

Pharmacokinetics

Absorption: 21% absorbed following oral administration.

Distribution: Unknown.

Metabolism and Excretion: Extensively metabolized; 40% by CYP3A4, remainder by other systems including CYP2D6. 29–51% excreted in urine, 44–77% excreted in feces, mostly as metabolites. <2.5% excreted in urine unchanged, <5% excreted in feces unchanged.

Half-life: 37 hr.

TIME/ACTION PROFILE (improvement in progression-free interval)

ROUTEONSETPEAKDURATION
PO2 mo6–8 mo14–18 mo

Contraindication/Precautions

Contraindicated in:

  • Severe hepatic impairment
  • Recent MI or unstable angina
  • Concurrent use of CYP3A4 inducers (may ↓ effectiveness)
  • Concurrent use of antiarrhythmics or QT-interval prolonging drugs (↑ risk of serious cardiovascular reactions)
  • Concurrent use of CYP2D6 substrates (alteration of blood levels may result in serious adverse effects)
  • OB: May cause fetal harm
  • Lactation:Discontinue breastfeeding or discontinue panobinostat.

Use Cautiously in:

  • Electrolyte abnormalities (↑ risk of cardiac toxicity, correct prior to treatment)
  • Mild/moderate hepatic impairment (↓ dose recommended)
  • End stage renal disease/dialysis
  • Geri: ↑ risk of adverse cardiac, GI and hematologic reactions (more frequent monitoring recommended);
  • Rep: Women of reproductive potential and sexually active men;
  • Pedi: Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: fatigue, weakness, dizziness, headache, syncope

Resp: cough, dyspnea, respiratory failure, rales, wheezing

CV: ARRHYTHMIAS, ISCHEMIA, QT INTERVAL PROLONGATION, hypertension, hypotension, orthostatic hypotension, palpitations, peripheral edema

GI: DIARRHEA, ↓ appetite, nausea, vomiting, abdominal distention, abdominal pain, cheilitis, colitis, dry mouth, dysgeusia, dyspepsia, flatulence, gastrointestinal pain, hepatic dysfunction

GU: renal impairment, urinary incontinence

Derm: erythema, rash, skin lesions

Endo: hyperglycemia, hypothyroidism

F and E: hypermagnesemia, hyperphosphatemia, hypocalcemia, hypokalemia, hypophosphatemia, dehydration, hypomagnesemia, hyponatremia

Hemat: BLEEDING, anemia, leukopenia, lymphopenia, neutropenia, thrombocytopenia

Metabolic: hyperuricemia

MS: joint swelling

Neuro: tremor

Misc: FEBRILE NEUTROPENIA, fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Drug-Food:

↑ blood levels and risk of toxicity with foods that are CYP3A inhibitors including grapefruit/grapefruit juice, pomegranate/pomegranate juice and star fruit; avoid these foods.

Route/Dosage

PO: (Adults) 20 mg every other day for 3 doses every wk (days 1, 3, 5, 8, 10 and 12) for 2 wk of every 21–day cycle for 8 cycles; an additional 8 cycles may be added if there is clinical benefit without dangerous toxicity. Given concurrently with bortezomib and dexamethasone. Dose reduction/interruption/alteration/discontinuation may be required for gastrointestinal or hematologic toxicity. Concurrent use of strong CYP3A4 inhibitors– ↓ starting dose to 10 mg.

Hepatic Impairment
PO: (Adults) Mild hepatic impairment– ↓ starting dose to 15 mg, Moderate hepatic impairment– ↓ starting dose to 10 mg.

Availability

Capsules: 10 mg, 15 mg, 20 mg

Assessment

  • Monitor for diarrhea during therapy. At first sign of abdominal cramping, loose stools, or onset of diarrhea, medicate patient with antidiarrheals (loperamide). Assess and maintain hydration status. If patient has moderate diarrhea (4–6 stools/day), interrupt panobinostat until diarrhea is resolved, then restart at same dose. If patient has severe diarrhea (≥7 stools/day) and IV fluids or hospitalization is required, interrupt panobinostat until diarrhea is resolved, then restart at reduced dose. If life-threatening diarrhea occurs, permanently discontinue panobinostat.
  • Obtain ECG prior to and periodically during therapy as clinically indicated. QTcF must be <450 msec before starting therapy. Interrupt therapy if QTcF increases ≥480 msec. Correct any abnormal electrolyte levels. Discontinue panobinostat if QT prolongation does not resolve.
  • Monitor for nausea and vomiting. Consider administering prophylactic anti-emetics.If patient has severe nausea, interrupt panobinostat until nausea is resolved and restart at reduced dose. If severe, life-threatening vomiting occurs, interrupt panobinostat until vomiting is resolved and restart at reduced dose.
  • Assess for signs and symptoms of infection (fever, sweats or chills, cough, flu-like symptoms, shortness of breath, blood in phlegm, sores on body, warm or painful areas on body, feeling very tired ) during therapy. Institute anti-infective therapy and consider interruption of panobinostat therapy.

Lab Test Considerations:

    • Obtain pregnancy test prior to and periodically during therapy in patients with reproductive potential.
  • Monitor CBC prior to and at least weekly during therapy; more frequently in patients >65 years of age. Baseline platelet count must be at least 100 x 109 /L and baseline absolute neutrophil count (ANC) at least 1.5 x 109 /L. If platelet count is <50 x 109 /L, maintain dose and monitor platelet counts weekly. If platelet count is <50 x 109 /L with bleeding, interrupt panobinostat, monitor platelet counts weekly until ≥50 x 109, then restart at reduced dose (see Implementation). If platelet count is <25 x 109 /L, interrupt panobinostat, monitor platelet counts weekly until ≥50 x 109, then restart at reduced dose. Consider platelet transfusions. If ANC is 0.75–1.0 x 109 /L, maintain panobinostat dose. If ANC is 0.5–0.75 x 109 /L (2 or more occurrences), interrupt panobinostat until ANC ≥1.0 x 109 /L, then restart at same dose. If ANC is <1.0 x 109 /L with febrile neutropenia, interrupt therapy until febrile neutropenia resolves and ANC ≥1.09 /L, then restart at reduced dose (see Implementation). If ANC is <0.5 x 109 /L, interrupt until ANC is ≥1.0 x 109 /L, then restart at reduced dose. Consider growth factors. If hemoglobin level is <8 g/L, interrupt until hemoglobin is ≥10 g/L, then restart at reduced dose.
    • Monitor electrolytes including potassium, magnesium, and phosphate prior to and weekly during therapy to prevent dehydration and electrolyte imbalances.
    • Monitor liver function tests (AST, ALT, total bilirubin) prior to and periodically during therapy. If levels ↑, consider dose adjustments until levels return to normal or pretreatment level.

Potential Diagnoses

Implementation

  • Panobinostat is administered in combination with bortezomab and dexamethasone.
    • If dose reduction required, reduce dose of panobinostat in increments of 5 mg (20 mg to 15 mg, or 15 mg to 10 mg). If dosing is reduced below 10 mg given 3 times per week, discontinue panobinostat. Keep same treatment schedule (3-week treatment cycle) when reducing dose.
  • PO: Administer at same time each scheduled day without regard to food, with a whole cup of water. Swallow capsules whole; do not open, crush, or chew. If patient vomits, do not repeat dose but take next usual scheduled dose.

Patient/Family Teaching

  • Instruct patient to take panobinostat as directed. Take missed dose as soon as possible within 12 hrs or wait until next scheduled dose. If vomiting occurs, do not repeat dose, take next dose at scheduled time. Advise patient to read Medication Guide prior to starting and with each Rx refill in case of changes.
  • Caution patient to avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice during therapy.
  • Advise patient to notify health care professional immediately if signs and symptoms of heart problems (chest pain or discomfort, changes in heart beat (fast or slow), palpitations, lightheadedness, fainting, dizziness, blue discoloration of lips, shortness of breath, swelling of lower limbs or skin), bleeding (blood in stools or black stools, pink or brown urine, unexpected bleeding or severe uncontrollable bleeding, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, feeling dizzy or weak, confusion, change in speech, headache that lasts a long time), infection, GI toxicities (nausea, vomiting, diarrhea, dehydration) or liver problems (feel tired or weak, loss of appetite, dark amber colored urine, upper abdominal (stomach) pain, yellowing of skin or white of eyes) occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications during therapy.
  • Rep: Caution female patient that panobinostat is teratogenic. Use effective contraception during and for at least 3 mo after therapy and avoid breastfeeding. Advise male patient to use condoms during and for at least 6 mo after last dose of panobinostat. Advise patient to notify health care professional if pregnancy occurs during therapy.
  • Emphasize the need for lab tests periodically during therapy to monitor for adverse reactions.

Evaluation/Desired Outcomes

Slowed progression of multiple myeloma.

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Citation

Quiring, Courtney, et al. "Panobinostat." Davis's Drug Guide, 16th ed., F.A. Davis Company, 2019. Anesthesia Central, anesth.unboundmedicine.com/anesthesia/view/Davis-Drug-Guide/110372/all/panobinostat.
Quiring C, Sanoski CA, Vallerand AH. Panobinostat. Davis's Drug Guide. 16th ed. F.A. Davis Company; 2019. https://anesth.unboundmedicine.com/anesthesia/view/Davis-Drug-Guide/110372/all/panobinostat. Accessed April 23, 2019.
Quiring, C., Sanoski, C. A., & Vallerand, A. H. (2019). Panobinostat. In Davis's Drug Guide. Available from https://anesth.unboundmedicine.com/anesthesia/view/Davis-Drug-Guide/110372/all/panobinostat
Quiring C, Sanoski CA, Vallerand AH. Panobinostat [Internet]. In: Davis's Drug Guide. F.A. Davis Company; 2019. [cited 2019 April 23]. Available from: https://anesth.unboundmedicine.com/anesthesia/view/Davis-Drug-Guide/110372/all/panobinostat.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - panobinostat ID - 110372 A1 - Quiring,Courtney, AU - Sanoski,Cynthia A, AU - Vallerand,April Hazard, BT - Davis's Drug Guide UR - https://anesth.unboundmedicine.com/anesthesia/view/Davis-Drug-Guide/110372/all/panobinostat PB - F.A. Davis Company ET - 16 DB - Anesthesia Central DP - Unbound Medicine ER -