Panobinostat Lactate

Multiple Myeloma

In combination with bortezomib and dexamethasone for treatment of multiple myeloma in patients who have received ≥2 prior therapies, including bortezomib and an immunomodulatory agent1 2 (designated an orphan drug by FDA for use in this condition3 ).

Accelerated approval based on progression-free survival; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

General

• Perform ECG prior to initiation of therapy to confirm that QT interval (corrected for heart rate using Fridericia's formula; QTcF) is <450 msec.1 Also determine serum concentrations of electrolytes, including potassium and magnesium, prior to initiation of therapy and correct any abnormalities.1 (See Cardiac Effects under Cautions.)

• Determine CBC prior to initiation of therapy to verify that baseline platelet count is ≥100,000/mm3 and ANC is ≥1500/mm3.1 (See Hematologic Effects under Cautions.)

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Restricted Distribution

• Obtain panobinostat through a limited network of specialty pharmacies.8 Contact manufacturer at 888-669-6682 or for specific availability information.8

Administration

Oral Administration

Administer once daily on each scheduled day at approximately the same time; administer without regard to food.1

Swallow capsules whole with a cup of water; do not open, crush, or chew capsules.1

Avoid exposure to capsule contents, including exposure to crushed or broken capsules.1 If such contact with the skin or mucous membranes occurs, wash affected areas thoroughly.1

Dosage

Available as panobinostat lactate; dosage expressed in terms of panobinostat.1

Adults

Administer in 21-day cycles in combination with IV bortezomib and oral dexamethasone.1

Cycles 1–8: Panobinostat 20 mg 3 times weekly during weeks 1 and 2 (days 1, 3, 5, 8, 10, and 12) of each cycle.1 Administer in combination with bortezomib 1.3 mg/m2 twice weekly during weeks 1 and 2 (days 1, 4, 8, and 11) and dexamethasone 20 mg 4 times weekly during weeks 1 and 2 (days 1, 2, 4, 5, 8, 9, 11, and 12) of each cycle.1

Consider continuing treatment for 8 additional cycles (cycles 9–16) in patients who derive clinical benefit and do not experience unresolved severe or clinically important toxicity.1

Cycles 9–16: Panobinostat 20 mg 3 times weekly during weeks 1 and 2 (days 1, 3, 5, 8, 10, and 12) of each cycle.1 Administer in combination with reduced IV bortezomib and oral dexamethasone dosages: bortezomib 1.3 mg/m2 once weekly during weeks 1 and 2 (days 1 and 8) and dexamethasone 20 mg twice weekly during weeks 1 and 2 (days 1, 2, 8, and 9) of each cycle.1

Total duration of treatment may be up to 16 cycles (48 weeks).1

Reduce initial panobinostat dose to 10 mg in patients receiving a potent CYP3A inhibitor.1 (See Interactions.)

Management of adverse effects may require treatment interruption with or without dosage reductions.1

If dosage reduction is necessary, reduce panobinostat dose in decrements of 5 mg while maintaining the 3-week treatment cycle.1 Discontinue panobinostat if reduction in dosage to <10 mg 3 times weekly is required.1

Grade 2 diarrhea (increase of 4–6 stools per day over baseline): Interrupt panobinostat therapy; also consider interruption of bortezomib therapy.1 Once diarrhea has resolved, may resume therapy with both drugs at the previous dosages.1 (See GI Effects under Cautions.)

Grade 3 diarrhea (increase of ≥7 stools per day over baseline) or need for IV fluids or hospitalization: Interrupt therapy with both panobinostat and bortezomib; once diarrhea has resolved, may resume therapy with both drugs at reduced dosages.1

Grade 4 (life-threatening) diarrhea: Permanently discontinue panobinostat and bortezomib.1

Grade 3 or 4 nausea or vomiting: Interrupt panobinostat therapy; once nausea and vomiting have resolved, may resume panobinostat at reduced dosage.1

QTcF interval ≥480 msec: Interrupt panobinostat therapy and correct any electrolyte abnormalities.1 If QT interval prolongation does not resolve, permanently discontinue panobinostat.1

Grade 3 thrombocytopenia (platelet count 25,000 to <50,000/mm3): May continue panobinostat and bortezomib at current dosages, with monitoring of platelet counts at least weekly.1

Grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia (platelet count <25,000/mm3): Interrupt therapy with both panobinostat and bortezomib and monitor platelet counts at least weekly.1 Once platelet count has recovered to ≥50,000/mm3, may resume panobinostat therapy at reduced dosage.1 Once platelet count is ≥75,000/mm3, may resume bortezomib at the previous dosage if only 1 dose was omitted prior to recovery or at a reduced dosage if ≥2 consecutive doses or ≥2 doses within the same cycle were omitted.1

If thrombocytopenia does not improve despite the recommended treatment modifications or despite repeated platelet transfusions, discontinue panobinostat.1

Grade 3 neutropenia with ANC 750–1000/mm3: May continue therapy with panobinostat and bortezomib.1

Following ≥2 occurrences of grade 3 neutropenia with ANC 500–750/mm3: Interrupt panobinostat therapy; may continue bortezomib at current dosage.1 Once ANC has recovered to ≥1000/mm3, may resume panobinostat therapy at the previous dosage.1

Grade 3 neutropenia with febrile neutropenia (any grade): Interrupt therapy with both panobinostat and bortezomib.1 Once febrile neutropenia has resolved and ANC has recovered to ≥1000/mm3, may resume panobinostat therapy at reduced dosage and may resume bortezomib therapy at the previous dosage if only 1 dose was omitted prior to recovery or at a reduced dosage if ≥2 consecutive doses or ≥2 doses within the same cycle were omitted.1

Grade 4 neutropenia (ANC <500/mm3): Interrupt therapy with both panobinostat and bortezomib.1 Once ANC has recovered to ≥1000/mm3, may resume therapy with panobinostat at reduced dosage and may resume bortezomib therapy at the previous dosage if only 1 dose was omitted prior to recovery or at a reduced dosage if ≥2 consecutive doses or ≥2 doses within the same cycle were omitted.1

If severe infection occurs or if neutropenia does not improve despite recommended treatment modifications and/or use of granulocyte colony-stimulating factors (G-CSFs), discontinue panobinostat.1

Grade 3 anemia (hemoglobin <8 g/dL): Interrupt panobinostat therapy.1 Once hemoglobin increases to ≥10 g/dL, may resume panobinostat therapy at reduced dosage.1

Grade 3 or 4 toxicity other than thrombocytopenia, neutropenia, or GI toxicity: Panobinostat dosage modification required.1 For grade 3 or 4 toxicity or for a grade 2 recurrence of such toxicity, interrupt panobinostat therapy; when toxicity has resolved to grade 1 or less, may resume panobinostat at reduced dosage.1 For grade 3 or 4 toxicity recurrence, may consider further dosage reduction once toxicity has resolved to grade 1 or less.1

Special Populations

Hepatic Impairment

Reduce initial panobinostat dose to 15 mg in patients with mild hepatic impairment and 10 mg in those with moderate hepatic impairment.1 (See Absorption: Special Populations, under Pharmacokinetics.) Frequently monitor patients for adverse effects; adjust dosage as needed for toxicity.1

Avoid use in patients with severe hepatic impairment.1

Renal Impairment

No special dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No special dosage recommendations.1 (See Geriatric Use under Cautions.)

Contraindications

• No known contraindications.1

Warnings/Precautions

Warnings

GI toxicity is common.1 Severe diarrhea reported in 25% of patients receiving panobinostat in combination with bortezomib and dexamethasone.1 Diarrhea may occur at any time during treatment.1

Monitor fluid and electrolyte status, including serum potassium, magnesium, and phosphate concentrations, prior to initiation of therapy and weekly (or more frequently as clinically indicated) during treatment; correct abnormalities to prevent dehydration and electrolyte disturbances.1

Initiate antidiarrheal therapy (e.g., loperamide) at first sign of abdominal cramping, loose stools, or onset of diarrhea.1 Ensure patients initiating treatment have antidiarrheal agents on hand.1

Consider prophylactic antiemetic therapy as clinically indicated.1

Patients who experience diarrhea, nausea, or vomiting may require treatment interruption or dosage reduction.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Severe or fatal cardiac ischemic events, severe arrhythmias, and ECG changes (e.g., QT interval prolongation, ST-segment depression, T-wave abnormalities) reported.1

Do not initiate in patients with a history of recent MI or unstable angina.1

Obtain ECG prior to initiation of therapy and periodically during treatment as clinically indicated.1 Monitor serum concentrations of electrolytes, including potassium and magnesium, prior to and during treatment; correct any abnormalities.1 During phase 3 clinical study in patients with relapsed multiple myeloma, ECGs were performed at baseline and prior to initiation of each cycle for cycles 1–8; serum electrolytes were monitored prior to beginning each cycle, at day 11 of cycles 1–8, and at the start of each cycle for cycles 9–16.1

Do not initiate in patients with QTcF interval >450 msec or clinically important ST-segment or T-wave abnormalities.1 If QTcF interval increases to ≥480 msec during treatment, interrupt panobinostat and correct any electrolyte abnormalities.1 Permanently discontinue if QT interval prolongation does not resolve.1

Other Warnings and Precautions

Serious, sometimes fatal, hemorrhage reported.1

Associated with severe thrombocytopenia, neutropenia, and anemia.1

Obtain CBC prior to initiation of therapy and monitor weekly (or more frequently if clinically indicated) during treatment.1 Monitor CBC more frequently in patients >65 years of age; increased frequency of myelosuppression observed in this age group.1

Treatment interruption or dosage reduction may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.) Consider platelet transfusions (for severe thrombocytopenia) and G-CSF use (for grade 3 or 4 neutropenia).1

Local and systemic infections, including pneumonia, bacterial infections, invasive fungal infections, and viral infections, reported.1

Do not initiate in patients with active infections.1

Monitor for signs and symptoms of infection during treatment.1 If infection develops, promptly initiate appropriate anti-infective treatment and consider interruption or discontinuance of treatment.1

Hepatic dysfunction, mainly elevations in aminotransferases and total bilirubin, reported.1

Monitor hepatic function prior to and regularly during treatment.1 May consider dosage modifications (see Hepatic Impairment under Dosage and Administration) if liver function test abnormalities are observed; monitor patient until concentrations return to normal or pretreatment values.1

May cause fetal harm; teratogenicity demonstrated in animals.1

Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Perform pregnancy test prior to initiation of therapy and periodically during treatment in women of childbearing potential.1

Sexually active women of childbearing potential should use effective contraception during therapy and for ≥1 month after the last dose.1 Sexually active men should use condoms during therapy and for 3 months after the last dose.1

Specific Populations

May cause fetal harm; teratogenicity demonstrated in animals.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in pediatric patients.1

No overall differences in efficacy relative to younger adults with relapsed multiple myeloma, but patients ≥65 years of age had a higher frequency of selected adverse effects, treatment discontinuance because of adverse effects (45 versus 30%), and death not related to disease progression (9 versus 5%) compared with younger adults.1 Monitor for toxicity (e.g., GI toxicity, myelosuppression, cardiac toxicity) more frequently in patients >65 years of age.1

Safety and efficacy not established in patients with hepatic impairment.1 Systemic exposure to panobinostat is increased.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Reduce initial dosage in patients with mild or moderate hepatic impairment; monitor frequently for adverse effects. Avoid use in patients with severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Mild to severe renal impairment did not alter systemic exposure.1 Not studied in patients with end-stage renal disease or patients undergoing dialysis.1

Common Adverse Effects

Decreased appetite,1 2 arrhythmia,1 diarrhea,1 2 fatigue,1 nausea,1 2 peripheral edema,1 2 pyrexia,1 2 vomiting,1 2 weight loss,1 2 anemia,1 2 Scr elevations,1 hyperbilirubinemia,1 hypermagnesemia,1 hyperphosphatemia,1 hypoalbuminemia,1 hypocalcemia,1 hypokalemia,1 hyponatremia,1 hypophosphatemia,1 leukopenia,1 2 lymphopenia,1 2 neutropenia,1 2 thrombocytopenia.1 2

Substrate of CYP3A; inhibits CYP2D6, 2C19, and 3A4 (time-dependent) in vitro.1 Does not inhibit CYP1A2, 2C8, 2C9, or 2E in vitro; does not induce CYP1A1/2, 2B6, 2C8/9/19, or 3A.1

Substrate of P-glycoprotein (P-gp); does not inhibit or induce P-gp in vitro.1

Does not induce uridine diphosphate-glucuronosyl transferase (UGT) 1A1 in vitro.1

Inhibits organic anion transporter (OAT) 3, organic anion transporter protein (OATP) 1B1 and 1B3, and organic cation transporter (OCT) 1 and 2 in vitro; does not inhibit breast cancer resistance protein (BCRP) or OAT1.1 Does not induce multidrug resistance protein (MRP) 2 transporters.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased panobinostat exposure;1 4 11 reduce initial panobinostat dose to 10 mg.1

Potent CYP3A inducers: Decreased panobinostat exposure is likely; avoid concomitant use.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Possible increased systemic exposure to the CYP2D6 substrate.1 4 Avoid concomitant use of panobinostat with sensitive CYP2D6 substrates or CYP2D6 substrates with a narrow therapeutic index.1 If concomitant use of panobinostat and CYP2D6 substrates cannot be avoided, frequently monitor patients for adverse reactions.1

CYP3A substrates: Possible increased systemic exposure to the CYP3A substrate; clinical relevance unknown.1 4

Drugs that Prolong QT Interval

Concomitant use with antiarrhythmics and other drugs known to prolong the QT interval not recommended.1 Manufacturer states that antiemetics that prolong the QT interval may be used concomitantly with frequent ECG monitoring.1

Drugs that Affect Gastric pH

Although aqueous solubility of panobinostat is pH dependent, simulations suggest changes in gastric pH will not substantially alter oral absorption.1 4

Specific Drugs and Foods

Absorption

Bioavailability

Absolute oral bioavailability approximately 21%.1 Peak concentrations achieved within 2 hours following oral administration.1

Food

Administration 30 minutes after a high-fat meal delayed peak plasma concentration by 2.5 hours and decreased peak concentration and AUC by 44 and 16%, respectively, compared with fasting conditions.1

Special Populations

Hepatic impairment increases panobinostat exposure.1 AUC increased by 43% in patients with mild hepatic impairment (bilirubin concentration at or below the ULN and AST concentration exceeding the ULN, or bilirubin concentration >1 to 1.5 times the ULN and any AST concentration) and by 105% in those with moderate hepatic impairment (bilirubin concentration >1.5 times but ≤3 times the ULN and any AST concentration).1

Mild to severe renal impairment does not substantially alter panobinostat exposure.1 4 Effect of end-stage renal disease or dialysis not established.1

Distribution

Extent

Not known whether distributed into milk.1

Plasma Protein Binding

Approximately 90%.1

Elimination

Metabolism

Extensively metabolized via reduction, hydrolysis, oxidation, and glucuronidation.1 CYP3A metabolism accounts for approximately 40% of the total hepatic elimination; minor contributions from CYP 2D6 and 2C19 observed in vitro.1 UGT 1A1, 1A3, 1A7, 1A8, 1A9, and 2B4 contribute to glucuronidation in vitro.1

Elimination Route

Excreted in feces (44–77%) and urine (29–51%); <3.5 and <2.5% of dose excreted as unchanged drug in feces and urine, respectively.1

Half-life

37 hours.1

Special Populations

Body surface area, gender, age, and race have no clinically meaningful effect on clearance.1