Posology : מינונים

4.2     Posology and method of administration

Treatment must be initiated and monitored under the supervision of physicians experienced in the management of multiple myeloma.

Dosing is continued or modified based upon clinical and laboratory findings (see section 4.4).

Posology
Pomalidomide in combination with bortezomib and dexamethasone
The recommended starting dose of pomalidomide is 4 mg taken orally once daily on Days 1 to 14 of repeated 21-day cycles.

Pomalidomide is administered in combination with bortezomib and dexamethasone, as shown in Table 1.
The recommended starting dose of bortezomib is 1.3 mg/m2 intravenous or subcutaneous once daily, on the days shown in Table 1. The recommended dose of dexamethasone is 20 mg taken orally once daily, on the days shown in Table 1.

Treatment with pomalidomide combined with bortezomib and dexamethasone should be given until disease progression or until unacceptable toxicity occurs.


Table 1. Recommended dosing scheme for pomalidomide in combination with bortezomib and dexamethasone

Cycle 1-8                                                            Day (of 21-day cycle) 1   2   3    4   5   6   7    8   9    10   11   12   13   14      15   16   17   18   19   20   21 Pomalidomide (4 mg)           •   •    •   •   •   •    •   •   •    •    •    •     •       • 2
Bortezomib (1.3 mg/m )        •            •                •             • Dexamethasone (20 mg) *       •   •        •   •            •   •         •    • 

Cycle 9 onwards                                                      Day (of 21-day cycle) 1   2   3    4   5   6   7    8   9    10   11   12   13   14      15   16   17   18   19   20   21 Pomalidomide (4 mg)           •   •    •   •   •   •    •   •   •    •    •    •     •       • 2
Bortezomib (1.3 mg/m )        •                             •
Dexamethasone (20 mg) *       •   •                         •   • 
* For patients > 75 years of age, see Special populations.

Pomalidomide dose modification or interruption
To initiate a new cycle of pomalidomide, the neutrophil count must be ≥ 1 x 109/l and the platelet count must be ≥ 50 x 109/l.
Instructions on dose interruptions or reductions for pomalidomide related adverse reactions are outlined in the Table 2 and dose levels are defined in Table 3 below:


Table 2. Pomalidomide dose modification instructions∞
Toxicity                                      Dose modification
Neutropenia*
• ANC** < 0.5 x 109/l or febrile           Interrupt pomalidomide treatment for neutropenia (fever ≥38.5°C and ANC    remainder of cycle. Follow CBC*** weekly.
9
<1 x 10 /l)
•     ANC return to ≥1 x 109/l                                Resume pomalidomide treatment at one dose level lower than previous dose.
•     For each subsequent drop < 0.5 x 109/l                  Interrupt pomalidomide treatment.

Resume pomalidomide treatment at one dose
• ANC return to ≥1 x 109/l                                      level lower than the previous dose.
Thrombocytopenia
• Platelet count <25 x 109/l                                    Interrupt pomalidomide treatment for remainder of cycle. Follow CBC*** weekly.

•     Platelet count return to ≥50 x 109/l                    Resume pomalidomide treatment at one dose level lower than previous dose.
•     For each subsequent drop <25 x 109/l                    Interrupt pomalidomide treatment.

Resume pomalidomide treatment at one dose
•     Platelet count return to ≥50 x 109/l                    level lower than the previous dose.

Rash                                                               Consider dose interruption or discontinuation Rash = Grade 2-3                                                   of pomalidomide treatment.

Rash = Grade 4 or blistering (including                            Permanently          discontinue         treatment       (see angioedema, anaphylactic reaction exfoliative                      section 4.4).
or bullous rash or if Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis
(TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected)
Other                                                              Interrupt pomalidomide treatment for Other ≥ Grade 3 pomalidomide-related                               remainder of cycle. Resume at one dose level adverse events                                                     lower than previous dose at next cycle (adverse event must be resolved or improved to ≤ Grade 2 before restarting dosing).
∞
Dose modification instructions in this table are applicable to pomalidomide in combination with bortezomib and dexamethasone and to pomalidomide in combination with dexamethasone.
*In case of neutropenia, the physician should consider the use of growth factors.
**ANC – Absolute Neutrophil Count;
***CBC – Complete Blood Count.


Table 3. Pomalidomide dose reduction∞
Dose level                        Oral pomalidomide dose
Starting dose                                      4 mg

Dose level -1                                      3 mg

Dose level -2                                      2 mg
Dose level -3                                      1 mg
∞
Dose reduction in this table is applicable to pomalidomide in combination with bortezomib and dexamethasone and to pomalidomide in combination with dexamethasone.


If adverse reactions occur after dose reductions to 1 mg, then the treatment should be discontinued.
Strong CYP1A2 inhibitors
If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered with pomalidomide, the dose of pomalidomide should be reduced by 50% (see sections 4.5 and 5.2).

Bortezomib dose modification or interruption
For instructions on dose interruptions or reductions for bortezomib related adverse reactions, physicians should refer to bortezomib Summary of Product Characteristics (SmPC).

Dexamethasone dose modification or interruption
Instructions on dose interruptions or reductions for low-dose dexamethasone related adverse reactions are outlined in Tables 4 and 5 below. However, dose interruption or resumption decisions are at the physician’s discretion per Summary of Product Characteristics (SmPC).

Table 4. Dexamethasone dose modification instructions
Toxicity                                        Dose Modification
Dyspepsia = Grade 1-2                                                  Maintain dose and treat with histamine (H2) blockers or equivalent. Decrease by one dose level if symptoms persist.

Interrupt dose until symptoms are controlled. Add H2
Dyspepsia ≥ Grade 3 blocker or equivalent and resume at one dose level lower than previous dose.
Oedema ≥ Grade 3                                                       Use diuretics as needed and decrease dose by one dose level.
Confusion or mood alteration ≥ Grade 2                                 Interrupt dose until symptoms resolve. Resume at one dose level lower than previous dose.
Muscle weakness ≥ Grade 2                                              Interrupt dose until muscle weakness ≤ Grade 1.
Resume at one dose level lower than previous dose.
Hyperglycaemia ≥ Grade 3                                               Decrease dose by one dose level. Treat with insulin or oral hypoglycaemic agents as needed.


Toxicity                                              Dose Modification Acute pancreatitis                                    Discontinue dexamethasone from treatment regimen.
Other ≥ Grade 3 dexamethasone-related adverse         Stop dexamethasone dosing until the adverse event events                                                resolves to ≤ Grade 2. Resume at one dose level lower than previous dose.

If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be resumed at one dose level lower than the previous dose.

Table 5. Dexamethasone dose reduction
≤ 75 years old                                 > 75 years old
Dose (Cycle 1-8: Days 1, 2, 4, 5, 8, 9,        Dose (Cycle 1-8: Days 1, 2, 4, 5, 8, 9, Dose Level              11, 12 of a 21-day cycle                       11, 12 of a 21-day cycle Cycle ≥ 9: Days 1, 2, 8, 9 of a 21-day         Cycle ≥ 9: Days 1, 2, 8, 9 of a 21-day cycle)                                         cycle)

Starting Dose                        20 mg                                       10 mg 
Dose Level -1                        12 mg                                        6 mg 
Dose Level -2                         8 mg                                        4 mg 

Dexamethasone should be discontinued if the patient is unable to tolerate 8 mg if ≤ 75 years old or 4 mg if > 75 years old.

In case of permanent discontinuation of any component of the treatment regimen, continuation of the remaining medicinal products is at the physician’s discretion.

Pomalidomide in combination with dexamethasone
The recommended starting dose of pomalidomide is 4 mg taken orally once daily on Days 1 to 21 of each 28-day cycle.

The recommended dose of dexamethasone is 40 mg taken orally once daily on Days 1, 8, 15 and 22 of each 28-day cycle.

Treatment with pomalidomide combined with dexamethasone should be given until disease progression or until unacceptable toxicity occurs.

Pomalidomide dose modification or interruption
Instructions for dose interruptions or reductions for pomalidomide related adverse reactions are outlined in Table 2 and 3.

Dexamethasone dose modification or interruption
Instructions for dose modification for dexamethasone related adverse reactions are outlined in Table 4.
Instructions for dose reduction for dexamethasone related adverse reactions are outlined in Table 6 below. However, dose interruption / resumption decisions are at physician’s discretion per the current Summary of Product Characteristics (SmPC).
Table 6. Dexamethasone dose reduction
≤ 75 years old                                  > 75 years old
Dose Level        Days 1, 8, 15 and 22 of each 28-day             Days 1, 8, 15 and 22 of each 28-day cycle                                            cycle

Starting Dose                        40 mg                                       20 mg 
Dose Level -1                        20 mg                                       12 mg 
Dose Level -2                        10mg                                         8 mg 

Dexamethasone should be discontinued if the patient is unable to tolerate 10 mg if ≤ 75 years old or 8 mg if > 75 years old.

Special populations

Elderly
No dose adjustment is required for pomalidomide.
Pomalidomide in combination with bortezomib and dexamethasone
For patients >75 years of age, the starting dose of dexamethasone is:
•     For Cycles 1 to 8: 10 mg once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each 21-day cycle
•     For Cycles 9 and onwards: 10 mg once daily on Days 1, 2, 8 and 9 of each 21-day cycle.

Pomalidomide in combination with dexamethasone
For patients >75 years of age, the starting dose of dexamethasone is 20 mg once daily on days 1, 8, 15 and 22 of each 28-day treatment cycle.

Hepatic impairment
Patients with serum total bilirubin > 1.5 x ULN (upper limit of normal range) were excluded from clinical studies. Hepatic impairment has a modest effect on the pharmacokinetics of pomalidomide (see section 5.2). No adjustment of the starting dose of pomalidomide is required for patients with hepatic impairment as defined by the Child-Pugh criteria. However, patients with hepatic impairment should be carefully monitored for adverse reactions and dose reduction or interruption of pomalidomide should be used as needed.

Renal impairment
No dose adjustment of pomalidomide is required for patients with renal impairment. On haemodialysis days, patients should take their pomalidomide dose following haemodialysis.

Paediatric population
There is no relevant use of pomalidomide in children aged 0-17 years for the indication of multiple myeloma.

Method of administration
Oral use.
Imnovid hard capsules should be taken orally at the same time each day. The capsules should not be opened, broken or chewed (see section 6.6). The capsules should be swallowed whole, preferably with water, with or without food. If the patient forgets to take a dose of pomalidomide on one day, then the patient should take the normal prescribed dose as scheduled on the next day. Patients should not adjust the dose to make up for a missing dose on previous days.

It is recommended to press only on one end of the capsule to remove it from the blister thereby reducing the risk of capsule deformation or breakage.