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, with radial 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 radial marking “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 adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent.

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)

Cycles 1-8 (3-week cycles)	Week 1 Days							Week 2 Days							Week 3
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 and dexamethasone (cycles 9-16)

Cycles 9-16 (3-week cycles)	Week 1 Days							Week 2 Days							Week 3
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. The baseline 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 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 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 baseline platelet count below 150 x 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 x 10⁹/l (complicated by bleeding) or <25 x 10⁹/l, Farydak therapy should be withheld and resumed at a reduced dose upon recovery to platelet 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 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

Thrombocytopenia grade on day of treatment	Modification of panobinostat starting dose	Panobinostat dose on recovery to grade 2 thrombocytopenia (≥50 x 109/l)	Modification of bortezomib starting dose	Bortezomib dose on recovery to grade 2 thrombocytopenia (≥50 x 109/l)
				1 dose omitted	More than 1 dose omitted
Grade 3 Platelets <50 x 109/l with bleeding	Omit dose	Resume at reduced dose	Omit dose	Resume at same dose	Resume at reduced dose
Grade 4 Platelets <25 x 109/l	Omit dose	Resume at reduced dose	Omit dose	Resume at same dose	Resume at reduced dose

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

Adverse drug reaction	Grade on day of treatment	Modification of panobinostat starting dose	Panobinostat dose on recovery to ≤ grade 1	Modification of bortezomib starting dose	Bortezomib dose on recovery to ≤ grade 1
Diarrhoea	Grade 2 despite anti-diarrhoeal medicinal product	Omit dose	Resume at the same dose	Omit dose	Resume at reduced dose or change to once weekly
	Grade 3 despite anti-diarrhoeal medicinal product	Omit dose	Resume at reduced dose	Omit dose	Resume at reduced dose or with the same dose but with a once-weekly schedule
	Grade 4 despite anti-diarrhoeal medicinal product	Permanently discontinue		Permanently discontinue

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

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