Panobinostat

Panobinostat is a histone deacetylase (HDAC) inhibitor that blocks the enzymatic activity of HDACs at nanomolar concentrations. HDACs remove acetyl groups from lysine residues of histones and of some other proteins, and they are overexpressed in multiple myeloma. Panobinostat is more cytotoxic to tumour cells than to normal cells.

Mechanism of Action

• HDAC inhibition: panobinostat inhibits class I, class II and class IV HDACs. These enzymes regulate the acetylation of a very large number of proteins involved in gene transcription, DNA repair, the cell cycle and protein degradation.
• Epigenetic effect: more acetylation of histones relaxes chromatin and leads to transcriptional activation. In tumour cells, panobinostat caused a dose-dependent rise in acetylation of histones H3 and H4 and higher expression of the tumour suppressor gene p21 (cyclin-dependent kinase inhibitor 1), a key mediator of G1 arrest and differentiation.
• Cell-cycle arrest and cell death: in vitro, the build-up of acetylated histones and other proteins induced cell-cycle arrest and/or apoptosis of some transformed cells.
• Synergy with bortezomib: laboratory data show cytotoxic synergy with the proteasome inhibitor bortezomib, the combination partner in the authorised regimen.
• Cardiac electrophysiology: panobinostat may prolong ventricular repolarisation (the QT interval); see Special Instructions.

Pharmacokinetics

• Absorption: rapid and almost complete, with peak concentrations within 2 hours of an oral dose; absolute oral bioavailability is about 21%. Exposure is linear between 10 and 30 mg and rises less than proportionally at higher doses. Food does not change overall exposure (AUC) but lowers the peak concentration by less than 45% and delays it by 1 to 2.5 hours, so the capsules can be taken with or without food.
• Distribution: about 90% bound to plasma proteins; the fraction in erythrocytes is 0.60 in vitro; volume of distribution at steady state about 1,000 L.
• Metabolism: extensive, and a large share of the dose is metabolised before it reaches the systemic circulation. The pathways are reduction, hydrolysis, oxidation and glucuronidation. Oxidation accounts for about 40% of the dose, mainly through CYP3A4 with minor CYP2D6 and CYP2C19 involvement. Unchanged panobinostat is only 6–9% of drug-related plasma exposure but is considered responsible for the overall activity. It is a P-glycoprotein (P-gp) substrate.
• Elimination: after a radiolabelled dose, 29–51% of the radioactivity was found in urine and 44–77% in faeces; unchanged drug was less than 2.5% of the dose in urine and less than 3.5% in faeces. Apparent renal clearance is 2.4–5.5 L/h and the terminal half-life is about 37 hours.
• Special populations: exposure rose by 43% in mild and by 105% (2-fold) in moderate hepatic impairment. It was unchanged in mild to severe renal impairment (not studied in end-stage renal disease or dialysis). Panobinostat was not evaluated in patients under 18 years.

• Multiple myeloma: in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent.

• Hypersensitivity to the active substance or to any of the excipients.
• Breast-feeding.

The safety data come mainly from the phase III Panorama 1 study, in which 381 patients with multiple myeloma received panobinostat 20 mg three times a week (two weeks on, one week off) with bortezomib and dexamethasone; the median exposure was 5.0 months. The most common non-haematological reactions were diarrhoea, fatigue, nausea and vomiting, and the haematological toxicities were thrombocytopenia, anaemia, neutropenia and lymphopenia. The frequencies below apply to the whole combination of panobinostat, bortezomib and dexamethasone; reactions linked to bortezomib or dexamethasone are described in their own SmPCs. The frequencies of the blood-cell disorders and of the electrolyte, bilirubin, creatinine and aminotransferase changes are based on laboratory values.

Very common (≥1/10): infections (upper respiratory tract infection, pneumonia); blood and lymphatic system (pancytopenia, thrombocytopenia, anaemia, leukopenia, neutropenia, lymphopenia); metabolism (decreased appetite, hypophosphataemia, hyponatraemia, hypokalaemia); insomnia; nervous system (dizziness, headache); hypotension; respiratory (cough, dyspnoea); gastrointestinal (diarrhoea, nausea, vomiting, abdominal pain, dyspepsia); general (fatigue, peripheral oedema, pyrexia, asthenia); weight decreased.

Common (≥1/100 to <1/10): infections (septic shock, urinary tract infection, viral infection, oral herpes, Clostridium difficile colitis, otitis media, cellulitis, sepsis, gastroenteritis, lower respiratory tract infection, candidiasis); hypothyroidism; metabolism (hyperglycaemia, dehydration, hypoalbuminaemia, fluid retention, hyperuricaemia, hypocalcaemia, hypomagnesaemia); nervous system (intracranial haemorrhage, syncope, tremor, dysgeusia); conjunctival haemorrhage; cardiac (bradycardia, atrial fibrillation, sinus tachycardia, tachycardia, palpitation); vascular (hypertension, haematoma, orthostatic hypotension); respiratory (respiratory failure, rales, wheezing, epistaxis); gastrointestinal (gastrointestinal haemorrhage, haematochezia, gastritis, cheilitis, abdominal distension, dry mouth, flatulence); hepatobiliary (abnormal hepatic function, hyperbilirubinaemia); skin (skin lesions, rash, erythema); joint swelling; renal and urinary (renal failure, haematuria, urinary incontinence); chills and malaise; investigations (increased blood urea, decreased glomerular filtration rate, increased alkaline phosphatase, QT prolongation on the ECG, increased creatinine, ALT and AST).

Uncommon (≥1/1,000 to <1/100): fungal pneumonia, hepatitis B, aspergillosis; myocardial infarction; haemorrhagic shock; pulmonary haemorrhage, haemoptysis; colitis, haematemesis, gastrointestinal pain; petechiae.

The SmPC table lists no rare, very rare or not known reactions.

Important serious reactions: grade 3 or 4 haemorrhage occurred in 4.2% of patients, including fatal gastrointestinal and pulmonary haemorrhage (five patients, 1.3%, died of events associated with haemorrhage). Severe and fatal infections (pneumonia, sepsis) were reported. Laboratory neutropenia occurred in 75% of patients (grade 3 in 28%, grade 4 in 6.6%), with febrile neutropenia in 1.0%; platelet transfusions were given to 33.3% of patients (10.3% with placebo). Cardiac events (most often atrial fibrillation, tachycardia and palpitation) occurred in 17.6% of patients against 9.8% with placebo plus bortezomib and dexamethasone, and syncope in 6.0% against 2.4%. QTcF values between 480 and 500 msec occurred in 1.3% of patients and none exceeded 500 msec. Adverse events led to discontinuation in 36.2% of patients, most often diarrhoea (4.5%), asthenia and fatigue (2.9% each) and pneumonia (1.3%). Deaths not due to myeloma occurred in 6.8% of patients against 3.2% with placebo, and in 8.8% of patients aged 65 or over against 5.4% of younger patients.

About 40% of panobinostat is metabolised by CYP3A4 and it is a P-gp substrate, so medicines that change CYP3A4 or P-gp activity can alter its levels.

• Strong CYP3A and/or P-gp inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole, nefazodone): ketoconazole raised the peak concentration 1.6-fold and the AUC 1.8-fold after a single 20 mg dose. The panobinostat dose is reduced to 10 mg (see Administration and Dosage); in hepatic impairment the combination should be avoided.
• Strong CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St John’s Wort): expected to lower exposure and efficacy; avoid. Dexamethasone, a mild-to-moderate dose-dependent CYP3A4 inducer, reduced panobinostat exposure by about 20% in myeloma studies.
• Medicines that prolong the QT interval: use with caution. Anti-emetics with a known risk of QT prolongation (dolasetron, granisetron, ondansetron, tropisetron) need particular care.
• Food and herbal products: avoid star fruit, grapefruit and grapefruit juice, and pomegranate and pomegranate juice, which inhibit CYP3A enzymes and may raise bioavailability. Avoid St John’s Wort.
• Hormonal contraceptives: dexamethasone given with panobinostat may reduce their effectiveness, and it is unknown whether panobinostat itself does; a barrier method must be added.
• Anticoagulants: extra attention to bleeding in patients on chronic anticoagulant therapy, because of the risk of thrombocytopenia.
• Laxatives: use with caution because they may worsen diarrhoea.
• Combination partners: the SmPCs of bortezomib and dexamethasone must also be consulted before treatment starts.

Treatment must be started by a physician experienced in the use of anti-cancer therapies. The capsules are taken once daily on the scheduled days only, at the same time each day, and are swallowed whole with water, with or without food. They must not be opened, crushed or chewed.

Recommended Dose and Schedule

• Panobinostat: 20 mg by mouth once daily on days 1, 3, 5, 8, 10 and 12 of a 21-day cycle. Patients are treated for eight cycles first; those with clinical benefit are advised to continue for eight more, so the total is up to 16 cycles (48 weeks).
• Bortezomib: 1.3 mg/m² as an injection. In cycles 1–8 it is given on days 1, 4, 8 and 11; in cycles 9–16 on days 1 and 8.
• Dexamethasone: 20 mg by mouth on a full stomach. In cycles 1–8 it is taken on days 1, 2, 4, 5, 8, 9, 11 and 12; in cycles 9–16 on days 1, 2, 8 and 9.
• The prescribing information of bortezomib and dexamethasone must be consulted before the combination starts, to assess whether a dose reduction of those medicines is needed.

Monitoring

• Blood counts: before starting and frequently during treatment, in particular before each bortezomib injection (days 1, 4, 8 and 11 of cycles 1–8; days 1 and 8 of cycles 9–16). At baseline platelets should be at least 100 ×10⁹/L and neutrophils at least 1.0 ×10⁹/L, and platelets should be at least 100 ×10⁹/L before any cycle. Extra counts in the rest period (for example days 15 and/or 18) should be considered, especially in patients aged 65 or over and those with baseline platelets below 150 ×10⁹/L.
• ECG: before starting and periodically before each cycle; QTcF must be below 480 msec before treatment begins.
• Electrolytes (potassium, magnesium, phosphorus): at baseline and periodically, especially in patients with diarrhoea; abnormal values are corrected.
• Liver function before treatment and regularly, especially in hepatic impairment; thyroid and pituitary function (for example free T4 and TSH) as clinically indicated.

Dose Adjustments for Side Effects

• Panobinostat is reduced in steps of 5 mg (20 mg to 15 mg to 10 mg), never below 10 mg, keeping the 3-week cycle.
• Thrombocytopenia: with platelets below 50 ×10⁹/L and bleeding, or below 25 ×10⁹/L, the dose is omitted and restarted at a reduced dose once platelets are back to at least 50 ×10⁹/L; platelets are checked at least twice a week until then. Bortezomib is also omitted and restarted at the same dose if one dose was missed, or at a reduced dose if more than one was missed. Treatment may be stopped if thrombocytopenia does not improve or repeated platelet transfusions are needed.
• Diarrhoea: grade 2 despite anti-diarrhoeals, the dose is omitted and resumed at the same dose on recovery to grade 1 or below; grade 3, omitted and resumed at a reduced dose; grade 4, permanent discontinuation. Grade 3 nausea or grade 3–4 vomiting despite an anti-emetic: stop temporarily and resume at a reduced dose on recovery to grade 1.
• Neutropenia: grade 3 (neutrophils from 0.5 to below 1.0 ×10⁹/L), the dose is omitted and resumed at the same dose on recovery to grade 2; grade 4 (below 0.5 ×10⁹/L) or febrile neutropenia (below 1.0 ×10⁹/L with fever of 38.5 °C or more), omitted and resumed at a reduced dose. Growth factors such as G-CSF should be considered, and stopping treatment may be considered if neutropenia does not improve or severe secondary infections occur.
• QTc prolongation: if QTcF is 480 msec or more at baseline, the start is delayed until the pre-dose average is below 480 msec, and abnormal potassium, magnesium or phosphorus is corrected. During treatment the dose is omitted if QTcF reaches 480 msec or more, or rises by more than 60 msec from baseline. If this resolves within 7 days, treatment resumes at the prior dose (first occurrence) or at a reduced dose (recurrence); if unresolved within 7 days it is discontinued, and any QTcF above 500 msec means permanent discontinuation.
• Other severe reactions: a recurrence of grade 2 toxicity, or any grade 3–4 toxicity, means omitting the dose until recovery to grade 1 or below and resuming at a reduced dose.

Special Populations

• Renal impairment: no starting dose change in mild to severe impairment; not studied in end-stage renal disease or dialysis.
• Hepatic impairment: mild, start with 15 mg in the first cycle (escalation to 20 mg may be considered); moderate, start with 10 mg in the first cycle (escalation to 15 mg may be considered); monitoring is more frequent. Severe impairment: panobinostat is not given, for lack of experience and safety data. The grades are defined by bilirubin and AST levels in the SmPC, which also advises considering a bortezomib dose adjustment.
• Elderly: patients over 65 are monitored more often for thrombocytopenia and gastrointestinal toxicity. Over 75, the starting doses or schedule may be adjusted: panobinostat 15 mg, raised to 20 mg in the second cycle if tolerated; bortezomib 1.3 mg/m² once weekly on days 1 and 8; dexamethasone 20 mg on days 1 and 8.
• Children and adolescents: no relevant use below 18 years in multiple myeloma.
• Strong CYP3A and/or P-gp inhibitors: the panobinostat dose is reduced to 10 mg; if the inhibitor is needed continuously, escalation to 15 mg may be considered according to tolerability. Such inhibitors should not be started in patients already on a reduced dose because of adverse reactions; if unavoidable, close monitoring is needed.

Missed or Vomited Dose

A missed dose can be taken up to 12 hours after the scheduled time. If vomiting occurs, no extra dose is taken; the next usual dose is taken as prescribed.

Blood Counts, Thrombocytopenia and Haemorrhage

Severe thrombocytopenia, neutropenia and anaemia (CTC grade 3–4) can occur. In the phase III study grade 3–4 thrombocytopenia began after a median of one month and recovered after a median of 12 days, usually to baseline by the next cycle. Haemorrhage, including fatal gastrointestinal and pulmonary haemorrhage, has been reported; patients with coagulation disorders or on chronic anticoagulation are at particular risk. Panobinostat may need to be withheld or reduced for platelets below 50 ×10⁹/L with bleeding, and platelet transfusions may be needed.

Infections

Localised and systemic infections have been reported, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including hepatitis B virus and herpes simplex. Some were severe and fatal. Treatment is not started in patients with active infection, and existing infections are treated first. Patients are monitored for signs of infection; appropriate anti-infective treatment is started promptly and interruption or discontinuation is considered. In invasive systemic fungal infection, panobinostat is stopped and anti-fungal therapy given.

Gastrointestinal Toxicity

Severe nausea, diarrhoea, constipation and vomiting can occur and may need anti-emetic and anti-diarrhoeal medicines. Fluid and electrolyte levels, especially potassium, magnesium and phosphate, are monitored and corrected to prevent dehydration. Prophylactic anti-emetics such as prochlorperazine may be considered; anti-emetics with a QT risk are used with caution. At the first sign of abdominal cramping, loose stools or diarrhoea, an anti-diarrhoeal such as loperamide is recommended, with intravenous fluids and electrolytes if needed. Laxatives are used with caution, and patients should speak to their physician before using one.

QT Prolongation and ECG Changes

Panobinostat may prolong the QT interval. No QTcF above 500 msec occurred at 20 mg in the phase III study; in pooled data from over 500 patients given panobinostat alone at various doses, QTcF above 500 msec occurred in about 1% overall and in 5% or more at doses of 60 mg or higher, with no torsade de pointes. ST-T depression (21.7%) and T wave changes (39.6%) were reported in the phase III study. Electrolytes and ECG are checked at baseline and periodically, particularly in severe gastrointestinal reactions. Caution is needed in patients with long QT syndrome or uncontrolled or significant cardiac disease (recent myocardial infarction, congestive heart failure, unstable angina, clinically significant bradycardia) and with other QT-prolonging medicines.

Liver and Thyroid

Hepatic dysfunction, mostly mild transient rises in aminotransferases and total bilirubin, has been reported; liver function is checked before and regularly during treatment. Hypothyroidism occurred in 8 of 381 patients (2 needed treatment), so thyroid and pituitary function is monitored as clinically indicated.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential need a pregnancy test before treatment and must use a highly effective contraceptive during treatment and for three months after the last dose. Women using hormonal contraceptives must also use a barrier method.
• Men: panobinostat can affect the quality of sperm formed during treatment. Sexually active men and their female partners must use a highly effective contraceptive during the man’s treatment and for six months after his last dose.
• Pregnancy: there are no clinical studies in pregnant patients. Animal studies show reproductive and embryo-foetal toxicity, and the risk to the foetus is predicted to be high. Panobinostat should be used in pregnancy only if the expected benefit outweighs the risk to the foetus.
• Breastfeeding: contraindicated.

Effect on Driving

Panobinostat has a minor influence on the ability to drive and use machines. Dizziness may occur.

Do not store Farydak capsules above 30 °C. Keep them in the original package to protect them from moisture. They are supplied in PVC/PCTFE/aluminium blisters of 6 capsules, in packs of 6, 12 or 24 (not all pack sizes may be marketed). No cold chain is needed.

4 years.

Prescription only (Rx). Treatment must be started by a physician experienced in the use of anti-cancer therapies. The capsules are taken at home, so they are supplied to the patient or to the treating clinic on prescription.