FARYDAK 15mg capsules medication leaflet

Farydak 10 mg hard capsules

Farydak 15 mg hard capsules

Farydak 20 mg hard capsules

Farydak 10 mg hard capsules

Each hard capsule contains panobinostat lactate anhydrous equivalent to 10 mg panobinostat.

Farydak 15 mg hard capsules

Each hard capsule contains panobinostat lactate anhydrous equivalent to 15 mg panobinostat.

Farydak 20 mg hard capsules

Each hard capsule contains panobinostat lactate anhydrous equivalent to 20 mg panobinostat.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Farydak 10 mg hard capsules

Light green opaque hard gelatin capsule (15.6-16.2 mm) containing white to almost white powder,with radial marking “LBH 10 mg” in black ink on cap and two radial bands in black ink on body.

Farydak 15 mg hard capsules

Orange opaque hard gelatin capsule (19.1-19.7 mm) containing white to almost white powder, withradial marking “LBH 15 mg” in black ink on cap and two radial bands in black ink on body.

Farydak 20 mg hard capsules

Red opaque hard gelatin capsule (19.1-19.7 mm) containing white to almost white powder, with radialmarking “LBH 20 mg” in black ink on cap and two radial bands in black ink on body.

Farydak, in combination with bortezomib and dexamethasone, is indicated for the treatment of adultpatients with relapsed and/or refractory multiple myeloma who have received at least two priorregimens including bortezomib and an immunomodulatory agent.

Treatment with Farydak should be initiated by a physician experienced in the use of anti-cancertherapies.

The recommended starting dose of panobinostat is 20 mg, taken orally once a day, on days 1, 3, 5, 8,10 and 12 of a 21-day cycle. Patients should be treated initially for eight cycles. It is recommendedthat patients with clinical benefit continue the treatment for eight additional cycles. The total durationof treatment is up to 16 cycles (48 weeks).

Panobinostat is administered in combination with bortezomib and dexamethasone, as shown in

Tables 1 and 2. The bortezomib and dexamethasone prescribing information should be consulted priorto the start of the combination treatment to assess whether a dose reduction is required.

The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose ofdexamethasone is 20 mg taken orally on a full stomach.

Table 1 Recommended dosing schedule of panobinostat in combination with bortezomib anddexamethasone (cycles 1-8)

Cycles 1-8 Week 1 Week 2 Week 3(3-week cycles) Days Days

Farydak 1 3 5 8 10 12 Rest period

Bortezomib 1 4 8 11 Rest period

Dexamethasone 1 2 4 5 8 9 11 12 Rest period

Table 2 Recommended dosing schedule of panobinostat in combination with bortezomib anddexamethasone (cycles 9-16)

Cycles 9-16 Week 1 Week 2 Week 3(3-week cycles) Days Days

Farydak 1 3 5 8 10 12 Rest period

Bortezomib 1 8 Rest period

Dexamethasone 1 2 8 9 Rest period

Monitoring recommendations

Blood cell counts

A complete blood cell count must be performed before initiating treatment with panobinostat. Thebaseline platelet count should be ≥100 x 109/l and the baseline absolute neutrophil count (ANC)≥1.0 x 109/l. Complete blood counts should be frequently monitored during treatment (in particularbefore each injection of bortezomib, i.e. on days 1, 4, 8 and 11 of cycles 1 to 8 and on days 1 and 8 ofcycles 9 to 16), especially for thrombocytopenia (see section 4.4). Prior to initiating any cycle oftherapy with panobinostat in combination with bortezomib and dexamethasone, platelet count shouldbe at least ≥100 x 109/l (see section 4.4). Additional blood counts should be considered during the“rest period” - e.g. on days 15 and/or 18, especially in patients ≥65 years and patients with a baselineplatelet count below 150 x 109/l.

ECG

Panobinostat may increase the QTc interval (see section 4.4). Therefore an ECG should be recordedprior to the start of therapy and repeated periodically before each treatment cycle. QTcF should be<480 msec prior to initiation of treatment with panobinostat (see below section on dose adjustmentsand section 4.4).

Blood electrolytes

Blood electrolytes, especially potassium, magnesium and phosphorus, should be measured at baselineand monitored periodically as clinically indicated, especially in patients with diarrhoea. Abnormalvalues should be corrected as clinically indicated (see section 4.4).

Liver function should be monitored prior to treatment and regularly during treatment as clinicallyindicated, especially in patients with hepatic impairment (see section 4.4).

Thyroid function tests

Mild hypothyroidism was reported in patients treated with panobinostat + bortezomib +dexamethasone in Study D2308; some patients required treatment (see section 4.4). Thyroid andpituitary function should be monitored by measuring hormone levels (e.g. free T4 and TSH) asclinically indicated.

Modification of the treatment dose and/or schedule may be required based on individual tolerability.

Clinical judgement on how to continue the treatment should be exercised when a patient experiencesan adverse drug reaction.

If a dose reduction is required, the dose of panobinostat should be reduced by decrements of 5 mg (i.e.from 20 mg to 15 mg or from 15 mg to 10 mg). The dose should not be reduced below 10 mg and thesame treatment schedule (3-week treatment cycle) should be kept.

Platelet counts should be monitored prior to each dose of bortezomib (i.e. on days 1, 4, 8 and 11 ofcycles 1-8, see Table 1, and on days 1 and 8 of cycles 9-16, see Table 2). If patients experiencethrombocytopenia, panobinostat may need to be temporarily withheld and the subsequent dose mayneed to be reduced (see Table 3). In patients with platelet count <50 x 109/l (complicated by bleeding)or <25 x 109/l, Farydak therapy should be withheld and resumed at a reduced dose upon recovery toplatelet count ≥50 x 109/l. Platelet counts should be monitored at least twice a week until ≥50 x 109/l.

Platelet transfusions may be required, if clinically indicated (see section 4.4). Discontinuation oftreatment may be considered if thrombocytopenia does not improve despite the treatmentmodifications described below and/or the patient requires repeated platelet transfusions. Additionally,dose adjustment of bortezomib may be considered (see bortezomib SmPC and Table 3).

Table 3 Recommended dose modifications for thrombocytopenia

Thrombocytopenia Modification Panobinostat dose Modification Bortezomib dose ongrade on day of of on recovery to of recovery to grade 2treatment panobinostat grade 2 bortezomib thrombocytopeniastarting dose thrombocytopenia starting dose (≥50 x 109/l)(≥50 x 109/l) 1 dose Moreomitted than1 doseomitted

Grade 3 Omit dose Resume at reduced Omit dose Resume Resume at

Platelets <50 x 109/l dose at same reducedwith bleeding dose dose

Grade 4 Omit dose Resume at reduced Omit dose Resume Resume at

Platelets <25 x 109/l dose at same reduceddose dose

Gastrointestinal toxicity

Gastrointestinal toxicity is very common in patients treated with panobinostat. Patients whoexperience diarrhoea and nausea or vomiting may require temporary dose discontinuation or dosereduction as outlined in Table 4.

Table 4 Recommended dose modifications for gastrointestinal toxicity

Adverse Grade on day of Modification of Panobinostat Modification Bortezomibdrug treatment panobinostat dose on of dose onreaction starting dose recovery to bortezomib recovery to≤ grade 1 starting dose ≤ grade 1

Diarrhoea Grade 2 despite Omit dose Resume at the Omit dose Resume atanti-diarrhoeal same dose reduced dosemedicinal product or change toonce weekly

Grade 3 despite Omit dose Resume at Omit dose Resume atanti-diarrhoeal reduced dose reduced dosemedicinal product or with thesame dosebut with aonce-weeklyschedule

Grade 4 despite Permanently Permanentlyanti-diarrhoeal discontinue discontinuemedicinal product

At the first sign of abdominal cramping, loose stools or onset of diarrhoea, it is recommended that thepatient be treated with an anti-diarrhoeal medicinal product (e.g. loperamide).

In the event of grade 3 nausea or grade 3 or 4 vomiting despite administration of an anti-emetic,panobinostat should be temporarily discontinued and resumed at a reduced dose on recovery tograde 1.

Prophylactic anti-emetics should be administered at the discretion of the physician and in accordancewith local medical practice (see section 4.4).

Neutropenia may require temporary or permanent dose reduction. Instructions for dose interruptionsand reductions for panobinostat are outlined in Table 5.

Table 5 Recommended dose modifications for neutropenia

Neutropenia grade Modification of Panobinostat dose Modification Bortezomibon day of treatment panobinostat on recovery to of dose onstarting dose grade 2 neutropenia bortezomib recovery to(<1.5-1.0 x 109/l) starting dose grade 2neutropenia(<1.5-1.0 x 109/l)

Grade 3 neutropenia Omit dose Resume at same dose Omit dose Resume at same(<1.0-0.5 x 109/l) dose

Grade 4 neutropenia Omit dose Resume at reduced Omit dose Resume at same(<0.5 x 109/l) or dose dosefebrile neutropenia(<1.0 x 109/l andfever ≥38.5°C)

In the event of grade 3 or 4 neutropenia, physicians should consider the use of growth factors (e.g.

G-CSF) according to local guidelines. Discontinuation of treatment may be considered if neutropeniadoes not improve despite the dose modifications and/or despite the addition of granulocyte colonystimulating factor therapy according to local medical practice and treatment guidelines, and/or in theevent of severe secondary infections.

QTc prolongation

In the event of long QT interval prior to initiation of panobinostat (QTcF ≥480 msec at baseline), thestart of treatment should be delayed until pre-dose average QTcF has returned to <480 msec. Inaddition any abnormal serum potassium, magnesium or phosphorus values should be corrected prior toinitiation of Farydak therapy (see section 4.4). In the event of QT prolongation during treatment:

* The dose should be omitted, if QTcF is ≥480 msec or above 60 msec from baseline.

* If QT prolongation is resolved within 7 days, resume treatment at prior dose for initialoccurrence or at reduced dose if QT prolongation is recurrent.

* If QT prolongation is unresolved within 7 days, treatment should be discontinued.

* If any QTcF value is above 500 msec, Farydak therapy should be permanently discontinued.

Other adverse drug reactions

For patients experiencing severe adverse drug reactions other than thrombocytopenia, gastrointestinaltoxicity, neutropenia or QTc prolongation, the recommendation is the following:

* CTC grade 2 toxicity recurrence or CTC grades 3 and 4 - omit the dose until recovery to CTCgrade ≤1 and resume treatment at a reduced dose.

* CTC grade 3 or 4 toxicity recurrence - a further dose reduction may be considered once theadverse reaction has resolved to CTC grade <1.

Plasma exposure of panobinostat is not altered in cancer patients with mild to severe renal impairment.

Therefore, starting dose adjustments are not necessary. Panobinostat has not been studied in patientswith end-stage renal disease (ESRD) or patients on dialysis (see section 5.2).

A clinical study in cancer patients with impaired hepatic function showed that plasma exposure ofpanobinostat increased by 43% (1.4-fold) and 105% (2-fold) in patients with mild and moderatehepatic impairment, respectively. Patients with mild hepatic impairment should be started onpanobinostat at a reduced dose of 15 mg during the first treatment cycle. A dose escalation from15 mg to 20 mg may be considered based on patient tolerability. Patients with moderate hepaticimpairment should be started on panobinostat at a reduced dose of 10 mg during the first treatmentcycle. A dose escalation from 10 mg to 15 mg may be considered based on patient tolerability.

Frequency of monitoring of these patients should be increased during treatment with panobinostat,particularly during the dose escalation phase. Panobinostat should not be administered in patients withsevere hepatic impairment due to lack of experience and safety data in this population. Adjustment ofbortezomib dose should also be considered (see bortezomib SmPC and Table 6).

Table 6 Recommended starting dose modification for patients with hepatic impairment

Grade of Bilirubin level SGOT Modification of Modification ofhepatic (AST) levels panobinostat starting bortezomib startingimpairment* dose dose

Mild ≤1.0 x ULN >ULN Reduce panobinostat None>1.0 x ULN and Any dose to 15 mg in the≤1.5 x ULN first treatment cycle.

Consider doseescalation up to 20 mgin subsequent cyclesbased on patienttolerability.

Moderate >1.5 x ULN and Any Reduce panobinostat Reduce bortezomib≤3.0 x ULN dose to 10 mg in the dose to 0.7 mg/m2 infirst treatment cycle. the first treatment

Consider dose cycle. Consider doseescalation up to 15 mg escalation toin subsequent cycles 1.0 mg/m2 or furtherbased on patient dose reduction totolerability. 0.5 mg/m2 insubsequent cyclesbased on patienttolerability.

SGOT = serum glutamic oxaloacetic transaminase;

AST = aspartate aminotransferase

ULN = upper limit of the normal range

* Based on NCI-CTEP classification

Patients over 65 years of age had a higher frequency of selected adverse reactions and ofdiscontinuation of treatment because of adverse reactions. It is recommended to monitor patients over65 years of age more frequently, especially for thrombocytopenia and gastrointestinal toxicity (seesections 4.4 and 4.8).

For patients >75 years of age, depending on the patient’s general condition and concomitant diseases,an adjustment of the starting doses or schedule of the components of the combination regimen may beconsidered. Panobinostat may be started at a dose of 15 mg, and if tolerated in the first cycle escalatedto 20 mg in the second cycle. Bortezomib may be started at 1.3 mg/m2 once weekly on days 1 and 8,and dexamethasone at 20 mg on days 1 and 8.

There is no relevant use of panobinostat in paediatric patients below the age of 18 years in theindication multiple myeloma (see section 5.2).

Strong CYP3A4 inhibitors

In patients who take concomitant medicinal products which are strong CYP3A and/or Pgp inhibitors,including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir,telithromycin, posaconazole and nefazodone, the dose of panobinostat should be reduced to 10 mg(see section 4.5). If continuous treatment with a strong CYP3A4 inhibitor is required, a dose escalationfrom 10 mg to 15 mg panobinostat may be considered based on patient tolerability.

In patients with hepatic impairment receiving concomitant medicinal products which are strong

CYP3A4 inhibitors, treatment with panobinostat should be avoided due to lack of experience andsafety data in this patient population.

Strong CYP3A inhibitors should not be started in patients who have already received a reduced doseof panobinostat due to adverse reactions. If this is unavoidable, patients should be closely monitoredand further dose reduction or discontinuation may be considered as clinically indicated (seesection 4.5).

Farydak should be administered orally once daily on scheduled days only, at the same time each day.

The capsules should be swallowed whole with water, with or without food (see section 5.2), and theyshould not be opened, crushed or chewed. If a dose is missed, it can be taken up to 12 hours after thespecified dose time. If vomiting occurs the patient should not take an additional dose, but should takethe next usual prescribed dose.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

Panobinostat is used in combination treatment, therefore the prescribing information of bortezomiband dexamethasone should be consulted prior to initiation of treatment with panobinostat.

Decrease in blood cell count

Haematological adverse drug reactions, including severe thrombocytopenia, neutropenia and anaemia(CTC grade 3 to 4) were reported in patients treated with panobinostat. Therefore a complete bloodcount must be performed before initiating therapy with panobinostat, with frequent monitoring duringtreatment (in particular before each injection of bortezomib as per bortezomib SmPC).

The platelet count should be ≥100 x 109/l and the absolute neutrophil count ≥1.0 x 109/l prior toinitiation of treatment. Platelet count should be ≥100 x 109/l prior to initiating any cycle of treatment(see section 4.2).

In the phase III study, thrombocytopenia typically recovered to baseline by the start of the next 21-daycycle (see Figure 1). The median time to onset for grade 3 and 4 thrombocytopenia was one month andthe median time to recovery was 12 days.

Figure 1 Median platelet counts over time (Study D2308, Safety set, cycles 1-8)(BL) 1:4 1:8 1:11 2:1 2:4 2:8 2:11 3:1 3:4 3:8 3:11 4:1 4:4 4:8 4:11 5:1 5:4 5:8 5:11 6:1 6:4 6:8 6:11 7:1 7:4 7:8 7:11 8:1 8:4 8:8 8:11

PAN+BTZ+Dex PBO+BTZ+Dex Cycle:Day

PA N+BTZ+Dex n= 381 370 367 363 351 342 335 320 323 310 298 283 285 265 268 250 253 232 238 225 230 206 206 199 205 183 188 175 185 159 170 155

PB O+BTZ+Dex n= 377 364 368 365 357 349 340 339 335 325 313 302 308 292 292 279 275 255 259 241 251 234 242 203 233 209 217 204 211 192 194 188

PAN=panobinostat

BTZ= bortezomib

Dex = dexamethasone

In patients with CTC grade 3 thrombocytopenia (platelet count <50 x 109/l with bleeding)panobinostat may need to be temporarily withheld and/or the subsequent dose may need to be reduced.

Platelet transfusions may be required as clinically indicated (see sections 4.2 and 4.8).

Haemorrhage has been reported in patients during treatment with panobinostat. CTC grade 3 or 4haemorrhage was reported in 4.2% of patients, including cases of gastrointestinal and pulmonaryhaemorrhage with fatal outcomes. Therefore, physicians and patients should be aware of the increasedrisk of thrombocytopenia and the potential for haemorrhage, especially in patients with coagulationdisorders or in those who are receiving chronic anti-coagulation therapy.

Infection

Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungalinfections such as aspergillosis or candidiasis, and viral infections including hepatitis B virus andherpes simplex, have been reported in patients taking panobinostat. Some of these infections (e.g.pneumonia) have been severe (e.g. leading to sepsis, or respiratory or multi-organ failure) and havehad fatal outcomes (see section 4.8). Of note, whereas grade 3 and grade 4 neutropenia were observedin 28% and 7% of patients, respectively, febrile neutropenia was observed in 1% of patients (seesection 4.8). Physicians and patients should be aware of the increased risk of infection withpanobinostat.

Farydak treatment should not be initiated in patients with active infections. Pre-existing infectionsshould be treated prior to initiation of the therapy. Patients should be monitored for signs andsymptoms of infections during treatment with panobinostat; if a diagnosis of infection is made,appropriate anti-infective treatment should be instituted promptly and interruption or discontinuationof Farydak considered.

If a diagnosis of invasive systemic fungal infection is made, panobinostat should be discontinued andappropriate anti-fungal therapy instituted.

Platelets 10 x 109/l

Severe nausea, diarrhoea, constipation and vomiting, sometimes requiring the use of anti-emetic andanti-diarrhoeal medicinal products, have been reported in patients treated with Farydak (seesection 4.8). Fluid and electrolyte blood levels, especially potassium, magnesium and phosphate,should be monitored periodically during therapy and corrected as clinically indicated to preventpotential dehydration and electrolyte disturbances (see section 4.2).

Prophylactic anti-emetics (e.g. prochlorperazine) may be considered at the discretion of the physicianand in accordance with local medical practice. Anti-emetic medicinal products with a known risk of

QT prolongation such as dolasetron, granisetron, ondansetron and tropisetron should be used withcaution (see section 4.5).

At the first sign of abdominal cramping, loose stools or onset of diarrhoea, it is recommended that thepatient be treated with anti-diarrhoeal medicinal product (e.g. loperamide) or any additional treatmentin accordance with local treatment guidelines. Replacement intravenous fluids and electrolytes may beused as appropriate. Medicinal products with laxative properties should be used with caution becauseof the potential for exacerbation of diarrhoea. Patients should be advised to contact their physician todiscuss the use of any laxative product.

Electrocardiographic changes

Panobinostat may prolong cardiac ventricular repolarisation (QT interval).

No episodes of QTcF prolongation >500 msec were reported with the dose of 20 mg Farydak in thephase III clinical study, in combination with bortezomib and dexamethasone. Pooled clinical data fromover 500 patients treated with panobinostat alone in multiple indications and at different dose levelshave shown that the incidence of CTC grade 3 QTc prolongation (QTcF >500 msec) wasapproximately 1% overall and 5% or more at a dose of 60 mg or higher; no episodes of torsades depointes were observed.

Additional analysis suggests that the risk of QTc prolongation does not increase over time (seesection 4.2).

QTcF should be <480 msec prior to initiation of treatment with Farydak.

Appropriate monitoring of electrolytes (e.g. potassium, magnesium and phosphorus) and ECG shouldbe performed at baseline and periodically during treatment, particularly in patients with severegastrointestinal adverse drug reaction (see section 4.2).

Farydak should be used with caution in patients who already have or who are at significant risk ofdeveloping QTc prolongation. This includes patients:

* with long QT syndrome.

* with uncontrolled or significant cardiac disease, including recent myocardial infarction,congestive heart failure, unstable angina or clinically significant bradycardia.

Concomitant administration of medicinal products that are known to cause QTc prolongation shouldbe used with caution (see section 4.5).

In case of concomitant use of agents that may increase panobinostat plasma concentrations, such asstrong CYP3A4 inhibitors, dose adjustment is required (see sections 4.5 and 4.2).

Hepatic dysfunction, primarily mild transient elevations in aminotransferases and total bilirubin, hasbeen reported in patients during treatment with panobinostat.

Liver function should be monitored prior to treatment and regularly during treatment. If results of liverfunction tests show abnormalities according to the NCI-CTEP classification, dose adjustments forpatients with mild and moderate hepatic impairment are recommended and the patient should befollowed until values return to normal or pre-treatment levels. Panobinostat should not be administeredin patients with severe hepatic impairment due to lack of experience and safety data in this population.

Adjustment of bortezomib dose should also be considered (see bortezomib SmPC and Table 6).

It is recommended to monitor patients over 65 years of age more frequently, especially forthrombocytopenia and gastrointestinal toxicity (see section 4.8 and section 4.2).

For patients >75 years of age, depending on the patient’s general condition and concomitant diseases,an adjustment of the starting doses or schedule of the components of the combination regimen may beconsidered (see section 4.2).

Strong inducers may reduce the efficacy of panobinostat, therefore the concomitant use of strong

CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin,rifampicin and St. John’s Wort (Hypericum perforatum), should be avoided (see section 4.5).

Women of childbearing potential taking panobinostat in combination with bortezomib anddexamethasone must use highly effective contraception for three months after stopping treatment (seesections 4.5 and 4.6 and bortezomib and dexamethasone SmPC). Women using hormonalcontraceptives should additionally use a barrier method of contraception.

Hypothyroidism events were reported in 8 of 381 patients treated with panobinostat + bortezomib +dexamethasone in Study D2308, of whom 2 required treatment. Thyroid and pituitary function shouldbe monitored by measuring hormone levels (e.g. free T4 and TSH) as clinically indicated (seesection 4.2).

Farydak metabolism is through both non-CYP and CYP mediated routes. Approximately 40% ofpanobinostat is metabolised through CYP3A4. Metabolism via CYP2D6 and 2C19 was minor.

Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter thepharmacokinetics of panobinostat. Panobinostat is a P-gp substrate.

Agents that may increase panobinostat plasma concentrations

Co-administration of a single 20 mg panobinostat dose with ketoconazole, a strong CYP3A inhibitor,increased the Cmax and AUC of panobinostat by 1.6- and 1.8-fold, respectively, compared to whenpanobinostat was given alone.

In patients who take concomitant medicinal products which are strong CYP3A and/or Pgp inhibitors,including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir,telithromycin, posaconazole and nefazodone, the dose of panobinostat should be reduced (seesection 4.2).

Patients should be instructed to avoid star fruit, grapefruit, grapefruit juice, pomegranates andpomegranate juice, as these are known to inhibit cytochrome P450 3A enzymes and may increase thebioavailability of panobinostat.

Agents that are predicted to decrease panobinostat concentrations

The panobinostat fraction metabolised through CYP3A4 is approximately 40%. In clinical studies inmultiple myeloma, the exposure of panobinostat was decreased by approximately 20% by theconcomitant use of dexamethasone, which is a dose-dependent mild/moderate CYP3A4 inducer.

Strong inducers are expected to have greater effects, and may reduce the efficacy of panobinostat,therefore the concomitant use of strong CYP3A4 inducers including, but not limited to,carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort (Hypericumperforatum), should be avoided.

Agents whose plasma concentrations may be increased by panobinostat

Panobinostat increased the Cmax and the AUC of dextromethorphan (a substrate of CYP2D6) by1.8- and 1.6-fold, respectively, and it cannot be excluded that the effect may be larger on a moresensitive CYP2D6 substrate. Avoid panobinostat use in patients who are taking CYP2D6 substrateswith a narrow therapeutic index (including, but not limited to, pimozide). When Farydak isco-administered with sensitive CYP2D6 substrates (e.g. atomoxetine, dextromethorphan, metoprolol,nebivolol, perphenazine and pimozide), dose titrate individual CYP2D6 substrates based ontolerability and frequently monitor patients for adverse reactions.

Agents whose plasma exposure can be decreased by panobinostat

It is currently unknown whether panobinostat may reduce the effectiveness of hormonalcontraceptives. In addition, when panobinostat is administered together with dexamethasone, which isknown to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, therisk for reduced efficacy of contraceptives needs to be considered. Women using hormonalcontraceptives should additionally use a barrier method of contraception.

No data is available that can be used to exclude the risk that panobinostat could be a weak inducer ofthe enzyme CYP3A4 in the gastrointestinal tract. This could potentially lead to slightly decreasedexposure to sensitive CYP3A4 substrates.

Anticipated pharmacodynamic interactions

Prolongation of QT interval

Based on preclinical and clinical data, panobinostat has the potential to prolong the QT interval.

Concomitant use of anti-arrhythmic medicinal products (including, but not limited to, amiodarone,disopyramide, procainamide, quinidine and sotalol) and other substances that are known to prolong the

QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, methadone,moxifloxacin, bepridil and pimozide) is not recommended. Anti-emetic medicinal products with aknown risk of QT prolongation such as dolasetron, granisetron, ondansetron and tropisetron should beused with caution (see section 4.4).

Women of child-bearing potential/Contraception in males and females

Based on findings in animals, the likelihood of panobinostat increasing the risk of both foetal deathand developmental skeletal abnormalities when administered to pregnant women is predicted to behigh. Women of child-bearing potential should have a pregnancy test prior to the initiation oftreatment with Farydak and must use a highly effective method of contraception during treatment andfor three months after the last dose of Farydak. Women using hormonal contraceptives shouldadditionally use a barrier method of contraception.

Due to its cytostatic/cytotoxic mode of action, panobinostat can influence the quality of sperm formedduring treatment. Sexually active men taking Farydak and their female partners should use a highlyeffective method of contraception during the man’s treatment and for six months after his last dose of

Farydak.

When panobinostat is administered together with dexamethasone, which is known to be a weak tomoderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacyof hormonal contraceptives needs to be considered. In addition, it is currently unknown whetherpanobinostat may reduce the effectiveness of hormonal contraceptives, and therefore women usinghormonal contraceptives should additionally use a barrier method of contraception.

There are no clinical studies on the use of Farydak in pregnant patients. Studies in animals have shownreproductive and embryo-foetal toxicity (see section 5.3). Given panobinostat’s cytostatic/cytotoxicmode of action, the potential risk to the foetus is high. Farydak should only be used during pregnancyif the expected benefits outweigh the potential risks to the foetus. If it is used during pregnancy or ifthe patient becomes pregnant while using it, the patient must be informed of the potential risk to thefoetus.

It is unknown whether panobinostat is excreted in human milk. Given its cytostatic/cytotoxic mode ofaction, breast-feeding is contraindicated during Farydak treatment (see section 4.3).

Based on non-clinical findings, male fertility may be compromised by treatment with Farydak (seesection 5.3).

Farydak has a minor influence on the ability to drive and use machines. Dizziness may occurfollowing administration of Farydak (see section 4.8).

The safety data of panobinostat have been assessed from a total of 451 patients with multiple myelomatreated with panobinostat in combination with bortezomib and dexamethasone and from a total of278 patients treated with panobinostat as a single agent.

The safety data reported below are based on the phase III clinical study (Panorama 1) in 381 patientswith multiple myeloma treated with 20 mg panobinostat once a day three times per week, on a2 weeks on and 1 week off dosing regimen in combination with bortezomib and dexamethasone.

The median duration of exposure in the study was 5.0 months. 15.7% of patients were exposed tostudy treatment for ≥48 weeks.

The most common non-haematological adverse reactions were diarrhoea, fatigue, nausea andvomiting.

Treatment-emergent haematological toxicities included thrombocytopenia, anaemia, neutropenia andlymphopenia.

QTcF >480 and <500 msec was recorded in 1.3% of patients and change from baseline of >60 msecwas observed in 0.8% of patients. No patient had an absolute QTcF >500 msec.

Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation and sinus tachycardia) werereported in 17.6% of panobinostat + bortezomib + dexamethasone-treated patients versus 9.8% ofplacebo + bortezomib + dexamethasone-treated patients and syncope events were reported in 6.0%versus 2.4%, respectively.

Discontinuation due to adverse events, regardless of causality, was observed in 36.2% of patients. Themost common adverse events (AEs) leading to treatment discontinuation were diarrhoea (4.5%),asthenia and fatigue (2.9% each) and pneumonia (1.3%).

On-treatment deaths not due to the study indication (multiple myeloma) were reported in 6.8% ofpanobinostat + bortezomib + dexamethasone-treated patients versus 3.2% of placebo + bortezomib +dexamethasone-treated patients.

Tabulated list of adverse drug reactions from clinical studies

Adverse drug reactions from the phase III study (Panorama 1) are shown in Table 7. Adverse drugreactions are listed according to system organ classes in MedDRA. Within each system organ class,the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within eachfrequency grouping, adverse drug reactions are presented in order of decreasing seriousness. Inaddition, the corresponding frequency category for each adverse drug reaction is based on thefollowing convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot beestimated from available data).

Table 7 includes adverse drug reactions that occur due to the addition of panobinostat to thebortezomib and dexamethasone combination. The frequency category reflects the combination of allthe medicinal products i.e. panobinostat + bortezomib + dexamethasone. For adverse drug reactionsthat are related to bortezomib or dexamethasone treatment, please refer to the relevant SmPC.

Table 7 Panobinostat adverse drug reactions observed in multiple myeloma patients in thephase III study

System Organ Class Frequency Adverse reaction

Infections and infestations Very common Upper respiratory tract infection, pneumonia

Common Septic shock, urinary tract infection, viralinfection, oral herpes, Clostridium difficilecolitis, otitis media, cellulitis, sepsis,gastroenteritis, lower respiratory tract infection,candidiasis

Uncommon Pneumonia fungal, hepatitis B, aspergillosis

Blood and lymphatic Very common Pancytopenia, thrombocytopenia, anaemia,system disorders a leukopenia, neutropenia, lymphopenia

Endocrine disorders Common Hypothyroidism

Metabolism and nutrition Very common Decreased appetite, hypophosphataemia a,disorders hyponatraemia a, hypokalaemia a

Common Hyperglycaemia, dehydration,hypoalbuminaemia, fluid retention,hyperuricaemia, hypocalcaemia,hypomagnesaemia

Psychiatric disorders Very common Insomnia

Nervous system disorders Very common Dizziness, headache

Common Haemorrhage intracranial, syncope, tremor,dysgeusia

Eye disorders Common Conjunctival haemorrhage

Cardiac disorders Common Bradycardia, atrial fibrillation, sinus tachycardia,tachycardia, palpitation

Uncommon Myocardial infarction

Vascular disorders Very common Hypotension

Common Hypertension, haematoma, orthostatichypotension

Uncommon Shock haemorrhagic

Respiratory, thoracic and Very common Cough, dyspnoeamediastinal disorders Common Respiratory failure, rales, wheezing, epistaxis

Uncommon Pulmonary haemorrhage, haemoptysis

Gastrointestinal disorders Very common Diarrhoea, nausea, vomiting, abdominal pain,dyspepsia

Common Gastrointestinal haemorrhage, haematochezia,gastritis, cheilitis, abdominal distension, drymouth, flatulence

Uncommon Colitis, haematemesis, gastrointestinal pain

Hepatobiliary disorders Common Hepatic function abnormal,hyperbilirubinaemia a

Skin and subcutaneous Common Skin lesions, rash, erythemadisorders Uncommon Petechiae

Musculoskeletal and Common Joint swellingconnective tissue disorders

Renal and urinary Common Renal failure, haematuria, urinary incontinencedisorders

General disorders and Very common Fatigue, oedema peripheral, pyrexia, astheniaadministration site Common Chills, malaiseconditions

Investigations Very common Weight decreased

Common Blood urea increased, glomerular filtration ratedecreased, blood alkaline phosphatase increased,electrocardiogram QT prolonged, bloodcreatinine increased a, SGPT alaninetransaminase (ALT) increased a, SGOT aspartatetransaminase (AST) increased aa Frequency is based on laboratory values

Description of selected adverse drug reactions

Gastrointestinal

Gastrointestinal toxicity, primarily diarrhoea, nausea and vomiting, is among the most frequentlyreported adverse reactions. However, treatment discontinuation due to these reactions was reported ina relatively small proportion of patients, with diarrhoea at 4.5% and nausea and vomiting at 0.5%each. Patients should be advised to contact their physician if severe gastrointestinal toxicity occurs anddose adjustment or discontinuation may be required (see section 4.4).

Due to the nature of multiple myeloma and the known haematotoxicity for panobinostat and itscombination agent bortezomib, thrombocytopenia, often severe, has been frequently observed. CTCgrade 3 or 4 thrombocytopenia occurred in 256 patients, with a median onset time of one month.

However, thrombocytopenia is reversible (median time to recovery of 12 days) and can usually bemanaged by dose adjustment and interruption with or without platelet transfusion (see section 4.4).33.3% patients in the panobinostat + bortezomib + dexamethasone arm and 10.3% patients in theplacebo + bortezomib + dexamethasone arm received platelet transfusions during treatment.

Thrombocytopenia rarely leads to treatment discontinuation (1.6% of patients). Most patients withthrombocytopenia did not experience haemorrhage. 20.7% of patients experienced haemorrhage, mostfrequently epistaxis (4.7%), haematoma (2.6%), and conjunctival haemorrhage (2.1%). CTC grade 3or 4 haemorrhage was reported in 4.2% of patients, mostly commonly involving gastrointestinalhaemorrhage. Five patients (1.3%) died of events associated with haemorrhage. Amongst the patientswho died of haemorrhage, one patient had thrombocytopenia grade 4, three patients hadthrombocytopenia grade 3 and 1 patient had thrombocytopenia grade 1.

Neutropenia was frequently reported on the basis of laboratory findings determined during the study(all grades: 75%). Most newly occurring severe neutropenia was grade 3 (28%), with considerablyfewer cases of grade 4 (6.6%). While many patients developed neutropenia, febrile neutropenia onlyoccurred in a fraction of treated patients (1.0%, both for CTC all grades and for grades 3 and 4).

Patients with neutropenia are prone to infection, mostly upper respiratory tract infection or pneumonia.

Only 0.3% of the patients were discontinued from the treatment due to neutropenia.

Fatigue and asthenia

Fatigue and asthenia were reported in 41.2% and 22.0% of patients, respectively. CTC grade 3 fatiguewas reported in 15.7% of the patients, and grade 4 in 1.3%. Grade 3 asthenia was observed in 9.4% ofthe patients, with no patients experiencing asthenia at CTC grade 4. The treatment was discontinued in2.9% of patients due to fatigue and asthenia.

Relapsed or refractory multiple myeloma patients are at risk of infections. Potential contributingfactors may include prior history of chemotherapy, stem cell transplant, the nature of the disease andneutropenia or lymphopenia associated with Farydak treatment. The most frequently reportedinfections include upper respiratory tract infection, pneumonia and nasopharyngitis. Fatalitiesinvolving either pneumonia or sepsis were reported. Treatment discontinuation due to infections wasreported in 5% of patients.

QT prolongation and ECG abnormalities

QTc prolongation was observed and was mostly mild in degree: QTcF interval >450 msec and≤480 msec was reported in 10.8% of patients, with maximum increase from baseline >30 msec and≤60 msec in 14.5% of patients. QTcF >500 msec was not reported in any patient.

ECG (electrocardiogram) abnormalities have been reported in patients treated with panobinostat +bortezomib + dexamethasone, mainly involving ST-T depression (21.7%) and T wave changes(39.6%). Regardless of events chronology, syncope was reported in 9% of patients with ST-Tdepression and 7.2% of patients with T wave change and 4.9% of patients with neither of these ECGabnormalities. Likewise ischaemic heart disease (including myocardial infarction and ischaemia) werereported in 4.5% of patients with ST-T depression and 4.8% of patients with T wave change and 2.7%of patients with neither of these ECG abnormalities.

The incidence of deaths not related to study indication was 8.8% in patients ≥65 years of agecompared to 5.4% in patients <65 years of age.

Adverse reactions leading to permanent discontinuation occurred in 30%, 44% and 47% of patientsaged <65 years, 65-75 years and ≥75 years, respectively. Grade 3-4 events more frequently observedin patients included the following (percentages presented for patients <65 years, 65-75 years and≥75 years of age, respectively): thrombocytopenia (60%, 74%, and 91%), anaemia (16%, 17% and29%), diarrhoea (21%, 27% and 47%), and fatigue (18%, 28% and 47%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Limited experience with overdose has been reported during clinical studies. Adverse reactionsobserved were consistent with the safety profile, with events primarily involving haematological andgastrointestinal disorders such as thrombocytopenia, pancytopenia, diarrhoea, nausea, vomiting andanorexia. Cardiac monitoring and assessment of electrolytes and platelet counts should be undertakenand supportive care given as necessary in the event of overdose. It is not known whether panobinostatis dialysable.

Pharmacotherapeutic group: Other antineoplastic agents, histone deacetylase (HDAC) inhibitors,

ATC code: L01XH03

Farydak is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs atnanomolar concentrations. HDACs catalyse the removal of acetyl groups from the lysine residues ofhistones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylationof histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading totranscriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones andother proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levelsof acetylated histones were observed in xenografts from mice that were treated with panobinostat.

Panobinostat shows more cytotoxicity towards tumour cells compared to normal cells.

Treatment of tumour cells with panobinostat resulted in a dose-dependent increase in acetylation ofhistones H3 and H4 both in vitro and in xenograft animal pre-clinical models, demonstrating targetinhibition. In addition, increased expression of the tumour suppressor gene p21CDKNIA (cyclindependent kinase inhibitor 1/p21) gene, a key mediator of G1 arrest and differentiation, was triggeredwith panobinostat exposure.

Clinical efficacy in patients with relapsed and relapsed and refractory multiple myeloma(Study D2308 - Panorama 1)

The efficacy and safety of panobinostat in combination with bortezomib and dexamethasone wereevaluated in a randomised, double-blind, placebo-controlled, multicentre phase III study in patientswith relapsed or relapsed and refractory multiple myeloma who had received 1-3 prior lines oftherapies.

Patients received panobinostat (20 mg taken orally once a day, three times per week, on a 2 weeks onand 1 week off dosing regimen), in combination with bortezomib (1.3 mg/m2 injected intravenously)and dexamethasone (20 mg). Treatment was administered for a maximum of 16 cycles (see Tables 1and 2).

A total of 768 patients were randomised in a 1:1 ratio to either the panobinostat + bortezomib +dexamethasone (n=387) or the placebo + bortezomib + dexamethasone (n=381) arm, stratified by prioruse of bortezomib [Yes (n=336 (43.8%)), No (n=432 (56.3%))] and number of prior lines ofanti-myeloma therapy [1 prior line (n=352 (45.8%)), 2 to 3 prior lines (n=416 (54.2%))].

Demographics and baseline disease characteristics were balanced and comparable between the studyarms.

The median age was 63 years, range 28-84; 42.1% of patients were older than 65 years. A total of53.0% of patients were male. Caucasians comprised 65.0% of the study population, Asians 30.2% andblacks 2.9%. ECOG performance status was 0-1 in 93% of patients. The median number of priortherapies was 1.0. More than half (57.2%) of the patients had undergone prior stem cell transplantationand 62.8% of the patients were relapsed after previous anti-neoplastic therapies (e.g. melphalan79.6%, dexamethasone 81.1%, thalidomide 51.2%, cyclophosphamide 45.3%, bortezomib 43.0%,combined bortezomib and dexamethasone 37.8%, lenalidomide 20.4%). More than one third (35.8%)of the patients were relapsed and refractory to prior treatment.

The median duration of follow-up was 28.75 months in the panobinostat + bortezomib +dexamethasone arm and 29.04 months in the placebo + bortezomib + dexamethasone arm.

The primary endpoint was progression free survival (PFS) as per modified European Bone Marrow

Transplant Group (mEBMT) criteria and as assessed by the investigator. In the overall patientpopulation PFS based on the full analysis set (FAS) was statistically significantly different betweenthe treatment arms (stratified Log-rank test p<0.0001, with an estimated 37% risk reduction in thepanobinostat + bortezomib + dexamethasone arm compared to the placebo + bortezomib +dexamethasone arm (Hazard ratio: 0.63 (95% CI: 0.52, 0.76)). The median PFS (95% CI) was12.0 months (10.3, 12.9) and 8.1 months (7.6, 9.2), respectively.

Overall survival (OS) was the key secondary endpoint. OS was not statistically significantly differentbetween the two treatment groups. The median OS was 40.3 months in the panobinostat + bortezomib+ dexamethasone arm and 35.8 months in the placebo + bortezomib + dexamethasone arm (Hazardratio: 0.94 (95% CI: 0.78, 1.14)).

Out of the pre-specified subgroup of patients with prior treatment with bortezomib and animmunomodulatory agent (N=193), 76% of patients had received at least two prior regimens. In thissubset of patients (N=147), the median duration of treatment was 4.5 months in the panobinostat +bortezomib + dexamethasone arm and 4.8 months in the placebo + bortezomib + dexamethasone arm.

The median PFS (95% CI) was 12.5 months (7.26, 14.03) in the panobinostat + bortezomib +dexamethasone arm and 4.7 months (3.71, 6.05) in the placebo + bortezomib + and dexamethasonearm [HR: 0.47 (0.31, 0.72)]. These patients had a median of 3 prior therapies. Efficacy results aresummarised in Table 8 and the Kaplan-Meier curves for PFS are provided in Figure 2.

Table 8 Progression-free survival in patients who received at least two prior regimensincluding bortezomib and an immunomodulating agent

Farydak Placebobortezomib and dexamethasone bortezomib and dexamethasone

N=73 N=74

Progression-free survival

Median, months [95% CI] 12.5 [7.26, 14.03] 4.7 [3.71, 6.05]

Hazard ratio [95% CI]1 0.47 (0.31, 0.72)1 Hazard ratio obtained from stratified Cox model

Figure 2 Kaplan-Meier plot of progression-free survival in patients with multiple myelomawho received at least two prior regimens including bortezomib and animmunomodulatory agent100 Hazard Ratio= 0.4795% CI [0.31; 0.72]

Logrank p-value=0.0003

Kaplan Meier medians

PAN+BTZ+Dex: 12.48 months

PBO+BTZ+Dex: 4.70 months

Censoring Times

P AN+BTZ+Dex (n/N=44/73)

PBO+BTZ+Dex (n/N=54/74)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Time (months)

Number of patients at risk

Time (months)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

PAN+BTZ+Dex 73 57 42 36 32 25 20 15 10 6 4 3 2 2 1 0

PBO+BTZ+Dex 74 54 37 23 11 9 5 4 2 2 2 2 2 0 0 0

PAN= panobinostat

PBO= placebo

BTZ= bortezomib

Dex = dexamethasone

In the subgroup of patients who had received at least two prior regimens including bortezomib and animmunomodulatory agent (n=147), the overall response rate using modified EBMT criteria was 59%in the panobinostat + bortezomib + dexamethasone arm and 39% in the placebo + bortezomib +dexamethasone arm. Response rates are summarised in Table 9.

Table 9 Response rates in patients with multiple myeloma who received at least two priorregimens including bortezomib and an immunomodulatory agent

Placebo

Farydak bortezomib andbortezomib and dexamethasone dexamethasone

N=73 N=74

Overall response 43 (59%) 29 (39%)[95% CI] (46.8, 70.3) (28, 51.2)

Complete response 6 (8%) 0

Near complete response 10 (14%) 6 (8%)

Partial response 27 (37%) 23 (31%)

Clinical efficacy in patients with bortezomib-refractory multiple myeloma (Study DUS71 -

Panorama 2)

Study DUS71 was a two-stage, single-arm, open-label multicentre phase II study of oral panobinostat(20 mg) in combination with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) in 55 patients withrelapsed and refractory multiple myeloma, who were bortezomib-refractory and had received at leasttwo prior lines of therapy. Patients had to be exposed to an IMiD (lenalidomide or thalidomide).

Refractoriness to bortezomib was defined as disease progression on or within 60 days of the lastbortezomib-containing line of therapy.

The primary endpoint of the study was to assess overall response rate (ORR) after 8 cycles of therapy

Progression-free survival Probability(%)as per mEBMT criteria.

Patients were heavily pre-treated and had received multiple prior regimens (median: 4; range: 2-11).

All 55 patients were previously treated with bortezomib and at least one IMiD (lenalidomide: 98.2%,thalidomide: 69.1%). The majority of patients had received prior transplant (63.6%).

The median duration of exposure to study treatment was 4.6 months (range: 0.1-24.1 months). Patientsachieved an ORR (≥PR (partial response)) of 34.5% and 52.7% (≥MR (minimal response)). Themedian time to response was 1.4 months and the median duration of response was 6.0 months. Themedian OS was 17.5 months.

The European Medicines Agency has waived the obligation to submit the results of studies with

Farydak in all subsets of the paediatric population in multiple myeloma (see section 4.2 forinformation on paediatric use).

Panobinostat is rapidly and almost completely absorbed with Tmax reached within 2 hours of oraladministration in patients with advanced cancer. The absolute oral bioavailability of panobinostat wasapproximately 21%. After oral administration, panobinostat pharmacokinetics appear to be linear inthe dose range 10-30 mg, but AUC increases less than proportionally with dose at higher doses.

Overall panobinostat exposure and inter-patient variability remained unchanged with or without food,whereas Cmax was reduced by <45% and Tmax prolonged by 1 to 2.5 hours with food (i.e. both normaland high-fat breakfasts). Since food did not alter overall bioavailability (AUC), panobinostat can beadministered regardless of food in cancer patients.

Panobinostat is moderately (approximately 90%) bound to human plasma proteins. Its fraction in theerythrocyte is 0.60 in vitro, independent of the concentration. The volume of distribution ofpanobinostat at steady state (Vss) is approximately 1,000 litres based on final parameter estimates inthe population pharmacokinetic analysis.

Panobinostat is extensively metabolised, and a large fraction of the dose is metabolised beforereaching the systemic circulation. Pertinent metabolic pathways involved in the biotransformation ofpanobinostat are reduction, hydrolysis, oxidation and glucuronidation processes. Oxidativemetabolism of panobinostat played a less prominent role, with approximately 40% of the doseeliminated by this pathway. Cytochrome P450 3A4 (CYP3A4) is the main oxidation enzyme, withpotential minor involvement of CYP2D6 and 2C19.

Panobinostat represented 6 to 9% of the drug-related exposure in plasma. The parent substance isdeemed to be responsible for the overall pharmacological activity of panobinostat.

After a single oral dose of [14C] panobinostat in patients, 29 to 51% of administered radioactivity isexcreted in the urine and 44 to 77% in the faeces. Unchanged panobinostat accounted for <2.5% of thedose in urine and <3.5% of the dose in faeces. The remainders are metabolites. Apparent panobinostatrenal clearance (CLR/F) was found to range from 2.4 to 5.5 l/h. Panobinostat has a terminal eliminationhalf-life of approximately 37 hours based on final parameters estimate in the population PK analysis.

Panobinostat was not evaluated in multiple myeloma patients under 18 years of age.

In the phase III clinical study 162 out of 387 patients were aged 65 years or over. Plasma exposure ofpanobinostat in patients aged 65 years or younger was similar to those older than 65 years in thepooling of single-agent panobinostat studies between the dose range of 10 mg and 80 mg.

The effect of hepatic impairment on the pharmacokinetics of panobinostat was evaluated in a phase Istudy, in 24 patients with solid tumours and with varying degrees of hepatic impairment. Mild andmoderate hepatic impairment as per NCI-CTEP classification increased panobinostat plasma exposureby 43% and 105%, respectively. No pharmacokinetic data are available for patients with severehepatic impairment.

The effect of renal impairment on the pharmacokinetics of panobinostat was assessed in a phase Istudy in 37 patients with advanced solid tumours with varying degrees of renal function. Mild,moderate and severe renal impairment based on baseline urinary creatinine clearance did not increasethe panobinostat plasma exposure in mild, moderate and severe groups.

Repeated dose toxicity studies

The primary target organs of toxicity following administration of panobinostat in rats and dogs wereidentified as the erythropoietic, myelopoietic and lymphatic systems. The thyroid changes includinghormones in dogs (decrease triodothyronine (T3)) and rats (decrease in triodothyronine (T3),tetraiodothyronine (T4) (males) and thyroid stimulating hormone (TSH)) were observed at exposurescorresponding to 0.07-2.2 of the human AUC observed clinically.

Carcinogenesis and mutagenesis

Carcinogenicity studies have not been performed with panobinostat. Panobinostat has demonstratedmutagenic potential in the Ames assay, endo reduplication effects in human peripheral bloodlymphocytes in vitro. Additionally, in vivo DNA damage was observed in a COMET study in mouselymphoma L5178Y cells and a dose-dependent molecular mechanisms study in murine bone marrowcells. The in vitro and in vivo findings are attributed to the pharmacological mode of action.

Reproduction toxicity

An increase in early resorptions was observed in female rats (doses ≥30 mg/kg). Prostatic atrophyaccompanied by reduced secretory granules, testicular degeneration, oligospermia and increasedepididymal debris were observed in dogs at exposures corresponding to 0.41-0.69 of the humanclinical AUC and not fully reversible after a 4 week recovery period.

Based on animal data, the likelihood of panobinostat increasing the risk of foetal death anddevelopmental skeletal abnormalities is predicted to be high. Embryo foetal lethality and increases inskeletal anomalies (extra sternabrae, extra ribs, increases in minor skeletal variations, delayedossification and variations of the sternabrae) were seen above exposures corresponding to 0.25 of thehuman clinical AUC.

The effects of panobinostat on labour and post-natal growth and maturation were not evaluated inanimal studies.

Magnesium stearate

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Farydak 10 mg hard capsules

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Iron oxide, yellow (E172)

Farydak 15 mg hard capsules

Gelatin

Titanium dioxide (E171)

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Iron oxide, red (E172)

Farydak 20 mg hard capsules

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Titanium dioxide (E171)

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Propylene glycol (E1520)

Shellac glaze

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4 years.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

PVC/PCTFE/Alu blister containing 6 capsules.

Packs containing 6, 12 or 24 capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

pharmaand GmbH

Taborstrasse 11020 Wien

Austria

Farydak 10 mg hard capsules

EU/1/15/1023/001-003

Farydak 15 mg hard capsules

EU/1/15/1023/004-006

Farydak 20 mg hard capsules

EU/1/15/1023/007-009

Date of first authorisation: 28 August 2015

Date of latest renewal: 28 April 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu