FARYDAK Hard capsule Ref.[9119] Active ingredients: Panobinostat

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

Posology

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 recommended that patients with clinical benefit continue the treatment for eight additional cycles. The total duration of 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 prior to 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 of dexamethasone is 20 mg taken orally on a full stomach.

Table 1. Recommended dosing schedule of panobinostat in combination with bortezomib and dexamethasone (cycles 1-8):

Table 2. Recommended dosing schedule of panobinostat in combination with bortezomib and dexamethasone (cycles 9-16):

Monitoring recommendations

Blood cell counts

A complete blood cell count must be performed before initiating treatment with panobinostat. The baseline platelet count should be ≥100 × 10⁹/l and the baseline absolute neutrophil count (ANC) ≥1.0 × 10⁹/l. Complete blood counts should be frequently monitored during treatment (in particular before each injection of bortezomib, i.e. on days 1, 4, 8 and 11 of cycles 1 to 8 and on days 1 and 8 of cycles 9 to 16), especially for thrombocytopenia (see section 4.4). Prior to initiating any cycle of therapy with panobinostat in combination with bortezomib and dexamethasone, platelet count should be at least ≥100 × 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 baseline platelet count below 150 × 10⁹/l.

ECG

Panobinostat may increase the QTc interval (see section 4.4). Therefore an ECG should be recorded prior 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 adjustments and section 4.4).

Blood electrolytes

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

Liver function tests

Liver function should be monitored prior to treatment and regularly during treatment as clinically indicated, 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 and pituitary function should be monitored by measuring hormone levels (e.g. free T4 and TSH) as clinically indicated.

Dose adjustments

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 experiences an 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 the same treatment schedule (3-week treatment cycle) should be kept.

Thrombocytopenia

Platelet counts should be monitored prior to each dose of bortezomib (i.e. on days 1, 4, 8 and 11 of cycles 1-8, see Table 1, and on days 1 and 8 of cycles 9-16, see Table 2). If patients experience thrombocytopenia, panobinostat may need to be temporarily withheld and the subsequent dose may need to be reduced (see Table 3). In patients with platelet count <50 × 10⁹/l (complicated by bleeding) or <25 × 10⁹/l, Farydak therapy should be withheld and resumed at a reduced dose upon recovery to platelet count ≥50 × 10⁹/l. Platelet counts should be monitored at least twice a week until ≥50 × 10⁹/l. Platelet transfusions may be required, if clinically indicated (see section 4.4). Discontinuation of treatment may be considered if thrombocytopenia does not improve despite the treatment modifications 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:

Gastrointestinal toxicity

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

Table 4. Recommended dose modifications for gastrointestinal toxicity:

At the first sign of abdominal cramping, loose stools or onset of diarrhoea, it is recommended that the patient 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 to grade 1.

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

Neutropenia

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

Table 5. Recommended dose modifications for neutropenia:

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 neutropenia does not improve despite the dose modifications and/or despite the addition of granulocyte colony stimulating factor therapy according to local medical practice and treatment guidelines, and/or in the event of severe secondary infections.

QTc prolongation

In the event of long QT interval prior to initiation of panobinostat (QTcF ≥480 msec at baseline), the start of treatment should be delayed until pre-dose average QTcF has returned to <480 msec. In addition any abnormal serum potassium, magnesium or phosphorus values should be corrected prior to initiation 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 initial occurrence 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, gastrointestinal toxicity, 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 CTC grade ≤1 and resume treatment at a reduced dose.

CTC grade 3 or 4 toxicity recurrence – a further dose reduction may be considered once the adverse reaction has resolved to CTC grade <1.

Special populations

Patients with renal impairment

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 patients with end-stage renal disease (ESRD) or patients on dialysis (see section 5.2).

Patients with hepatic impairment

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

Table 6. Recommended starting dose modification for patients with hepatic impairment:

SGOT = serum glutamic oxaloacetic transaminase;
AST = aspartate aminotransferase
ULN = upper limit of the normal range
* Based on NCI-CTEP classification

Elderly population

Patients over 65 years of age had a higher frequency of selected adverse reactions and of discontinuation of treatment because of adverse reactions. It is recommended to monitor patients over 65 years of age more frequently, especially for thrombocytopenia and gastrointestinal toxicity (see sections 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 be considered. Panobinostat may be started at a dose of 15 mg, and if tolerated in the first cycle escalated to 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.

Paediatric population

There is no relevant use of panobinostat in paediatric patients below the age of 18 years in the indication 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 escalation from 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 and safety data in this patient population.

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

Method of administration

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 they should not be opened, crushed or chewed. If a dose is missed, it can be taken up to 12 hours after the specified dose time. If vomiting occurs the patient should not take an additional dose, but should take the next usual prescribed dose.

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

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 local requirements.