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5     DOSAGE AND ADMINISTRATION
5.1 Recommended Dosage
Mantle Cell Lymphoma and Marginal Zone Lymphoma
The recommended dosage of IMBRUVICA for MCL and MZL is 560 mg orally once daily until disease progression or unacceptable toxicity.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s Macroglobulinemia The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily until disease progression or unacceptable toxicity.
For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with rituximab or Obinutuzumab (BR), or in combination with bendamustine and rituximab (BR), or in combination with venetoclax. In the co-morbid and elderly population the combination should be used with more caution In combination with venetoclax for the treatment of CLL, IMBRUVICA should be administered as a single agent for 3 cycles (1 cycle is 28 days), followed by 12 cycles of IMBRUVICA plus venetoclax. See the venetoclax Summary of Product Characteristics (SmPC) for full venetoclax dosing information.
For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab.
When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
Chronic Graft versus Host Disease
The recommended dosage of IMBRUVICA for cGVHD is 420 mg orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy 
 for the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical assessment of the individual patient.
Administration
Administer IMBRUVICA at approximately the same time each day with a glass of water.
Swallow tablets or capsule whole. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets.
If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Do not take extra doses of IMBRUVICA to make up for the missed dose.
5.2 DOSAGE MODIFICATIONS FOR ADVERSE REACTIONS


For adverse reactions listed in Table 1, interrupt IMBRUVICA therapy. Once the adverse reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage modifications (see Table 1).

Table 1: Recommended Dosage Modifications for Adverse Reactions
Dose Modification for                Dose Modification for
MCL and MZL After                    CLL/SLL, WM, and
Adverse Reactiona,b                   Occurrence                  Recovery                      cGVHD After Recovery Starting Dose = 560 mg               Starting Dose = 420 mg

First              Restart at 420 mg dailyc              Restart at 280 mg dailyc 
Grade 2 cardiac failure               Second             Restart at 280 mg dailyc              Restart at 140 mg dailyc 
Third              Discontinue IMBRUVICA                 Discontinue IMBRUVICA 
First              Restart at 420 mg dailyc              Restart at 280 mg dailyc Grade 3 cardiac arrhythmias
Second             Discontinue IMBRUVICA                 Discontinue IMBRUVICA 
Grade 3 or 4 cardiac failure
First              Discontinue IMBRUVICA                 Discontinue IMBRUVICA Grade 4 cardiac arrhythmias

Other Grade 3 or 4 non-               First              Restart at 420 mg daily               Restart at 280 mg daily hematological toxicitiesd
Grade 3 or 4 neutropenia              Second             Restart at 280 mg daily               Restart at 140 mg daily with infection or fever
Third              Discontinue IMBRUVICA                 Discontinue IMBRUVICA Grade 4 hematological toxicities a
See Warnings and Precautions (5).
b
Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL.
c
Evaluate the benefit-risk before resuming treatment.
d
For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.


5.3Dosage Modifications for Use with CYP3A Inhibitors
Recommended dosage modifications are described below [see Drug Interactions (10.1)]: 
Table 2: Recommended Dosage Modifications for Use with CYP3A Inhibitors 
Patient Population     Coadministered Drug                        Recommended IMBRUVICA Dosage
B-Cell            •   Moderate CYP3A inhibitor                 280 mg once daily Malignancies                                                   Modify dose as recommended [see Dosage and Administration (.2)].

•   Voriconazole 200 mg twice daily        140 mg once daily
•   Posaconazole suspension 100 mg         Modify dose as recommended [see once daily, 100 mg twice daily, or     Dosage and Administration (.2)].
200 mg twice daily
•   Other strong CYP3A inhibitors          Avoid concomitant use.
If these inhibitors will be used short- term (such as anti-infectives for seven days or less), interrupt IMBRUVICA.

Chronic Graft versus   •   Moderate CYP3A inhibitor               420 mg once daily Host Disease
Modify dose as recommended [see
Dosage and Administration (.2)].

•   Voriconazole 200 mg twice daily        280 mg once daily
•   Posaconazole suspension 100 mg         Modify dose as recommended [see once daily, 100 mg twice daily, or     Dosage and Administration (.2)].
200 mg twice daily

•   Posaconazole suspension 200 mg         140 mg once daily three times daily or 400 mg twice      Interrupt dose as recommended [see daily                                  Dosage and Administration (.2)].
•   Posaconazole intravenously 300 mg once daily
•   Posaconazole delayed-release tablets 300 mg once daily
•   Other strong CYP3A inhibitors          Avoid concomitant use.
If these inhibitors will be used short- term (such as anti-infectives for seven days or less), interrupt IMBRUVICA.
After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage and Administration (5.1), Drug Interactions (10.1)].
5.4      Dosage Modifications for Use in Hepatic Impairment
The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A).
Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations (11.6), Clinical Pharmacology (14.3)].


6     DOSAGE FORMS AND STRENGTHS
[See Pharmaceutical form (3)].