Posology : מינונים

4.2    Posology and method of administration

Posology
Treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases. Optzuro should be taken at the same time of day (e.g. in the morning or evening) with food, including when taking the dose less frequently than once daily.

Chronic liver disease

Obtain a platelet count prior to the administration of Optzuro therapy and on the day of a procedure to ensure an adequate increase in platelet count, and no unexpectedly high increase in platelet count in the patient populations specified in sections 4.4 and 4.5.

The recommended daily dose of avatrombopag is based on the patient’s platelet count (see Table 1).
Dosing should begin 10 to 13 days prior to the planned procedure. The patient should undergo their procedure 5 to 8 days after the last dose of avatrombopag.



Table 1: Daily dose recommendation for avatrombopag

Platelet count (x 109/L)               Once-daily dose                 Duration of dosing < 40                   60 mg (Three 20 mg tablets)                  5 days ≥ 40 to < 50                40 mg (Two 20 mg tablets)                   5 days 
Duration of treatment
Due to limited information, avatrombopag should not be taken for more than 5 days.

Missed doses
If a dose is missed, it should be taken as soon as it is remembered. Two doses should not be taken at one time to make up for a missed dose. The next dose should be taken at the usual time the next day.

Chronic immune thrombocytopenia

Use the lowest dose of Optzuro needed to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Do not use avatrombopag to normalise platelet counts. In clinical trials, platelet counts generally increased within 1 week after starting avatrombopag and decreased within 1 to 2 weeks after discontinuation.

Initial dose regimen
The recommended starting dose of Optzuro is 20 mg (1 tablet) once daily with food.

Monitoring and dose adjustment
After initiating therapy, assess platelet counts at least once weekly until a stable platelet count ≥ 50 x 109/L and ≤ 150 x 109/L has been achieved. Twice weekly platelet count monitoring should be conducted during the first weeks of therapy in patients receiving avatrombopag only once or twice weekly. Twice weekly monitoring should also be conducted after dose adjustments during the treatment.

Due to the potential risk of platelet counts above 400 x 109/L within the first weeks of treatment patients should be carefully monitored for any signs or symptoms of thrombocytosis. After a stable platelet count has been achieved, obtain platelet counts at least monthly. After discontinuation of avatrombopag, platelet counts should be obtained weekly for at least 4 weeks.

Dose adjustments (see Table 2 and Table 3) are based on the platelet count response. Do not exceed a daily dose of 40 mg (2 tablets).



Table 2: Avatrombopag dose adjustments for patients with primary chronic immune thrombocytopenia

Platelet count (x 109/L)              Dose adjustment or action
•          Increase One Dose Level per Table 3.
< 50 after at least 2 weeks of avatrombopag treatment                •          Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.
•          Decrease One Dose Level per Table 3.
> 150 and ≤ 250                       •          Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.
•          Stop avatrombopag.
•          Increase platelet monitoring to twice weekly.
> 250
•          When platelet count is less than 100 x 109/L,
decrease One Dose Level per Table 3 and reinitiate therapy.
< 50 after 4 weeks of                 •          Discontinue avatrombopag.
avatrombopag 40 mg once daily
> 250 after 2 weeks of
•          Discontinue avatrombopag.
avatrombopag 20 mg weekly


Table 3: Avatrombopag dose levels for titration in patients with primary chronic immune thrombocytopenia


Dose≠                                                                              Dose Level 40 mg once daily                                                                           6
40 mg three times a week AND 20 mg on the four remaining days of each week                 5
20 mg once daily*                                                                          4
20 mg three times a week                                                                   3
20 mg twice a week OR 40 mg once weekly                                                    2
20 mg once weekly                                                                          1
*Initial dose regimen for all patients except those taking moderate or strong dual inducers or moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5, or of CYP2C9 alone.
≠
Patients taking avatrombopag less frequently than once daily should take the medicinal product in a consistent manner from week to week.
Dose Level 3: Three non-consecutive days a week, e.g. Monday, Wednesday and Friday Dose Level 2: Two non-consecutive days a week, e.g. Monday and Friday Dose Level 1: The same day each week, e.g. Monday

In the case of a missed dose, patients should take the missed dose of avatrombopag as soon as they remember. Patients should not take two doses at one time to make up for a missed dose, and should take the next dose per the current regimen.

Avatrombopag can be administered in addition to other ITP medicinal products. Platelet counts should be monitored when combining avatrombopag with other medicinal products for the treatment of primary ITP in order to avoid platelet counts outside of the recommended range, and to determine whether the dose of either medicinal product should be reduced.

Discontinuation
Discontinue avatrombopag if the platelet count does not increase to ≥ 50 x 109/L after 4 weeks of dosing at the maximum dose of 40 mg once daily. Discontinue Optzuro if the platelet count is greater than 250 x 109/L after 2 weeks of dosing at 20 mg once weekly.

Recommended dose with concomitant moderate or strong dual inducers or inhibitors of CYP2C9 and CYP3A4/5, or of CYP2C9 alone, in patients with chronic immune thrombocytopenia The recommended starting doses of avatrombopag in patients with chronic immune thrombocytopenia receiving concomitant medicinal products are summarised in Table 4.

Table 4: Avatrombopag recommended starting dose for patients with primary chronic immune thrombocytopenia based on concomitant medications

Concomitant medicinal products                         Recommended starting dose Moderate or strong dual inhibitors of CYP2C9 and
20 mg (1 tablet) three times a week
CYP3A4/5, or of CYP2C9 alone (e.g., fluconazole)

Moderate or strong dual inducers of CYP2C9 and
CYP3A4/5, or of CYP2C9 alone (e.g., rifampicin,              40 mg (2 tablets) once daily enzalutamide)


Special populations
Elderly
No dose adjustment is required for patients aged 65 years and older (see section 5.2).

Renal impairment
Avatrombopag is not renally excreted, therefore no dose adjustment is required in patients with mild or moderate renal impairment. Avatrombopag has not been studied in patients with severe renal impairment (see section 5.2).

Hepatic impairment
No dose adjustment is necessary for patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment.

Due to limited information available, the safety and efficacy of avatrombopag in patients with severe hepatic impairment (Child-Pugh class C, MELD score > 24) have not been established (see section 4.4). No dose adjustment is expected for these patients. Avatrombopag therapy should only be initiated in patients with severe hepatic impairment if the expected benefit outweighs the expected risks (see sections 4.4 and 5.2).

Coexisting medical conditions
Due to limited or no information available, the safety and efficacy of avatrombopag in adult patients with chronic ITP and human immunodeficiency virus [HIV], hepatitis C virus [HCV] or subjects with known systemic lupus erythematosus, acute hepatitis, active chronic hepatitis, cirrhosis, lymphoproliferative disease, myeloproliferative disorders, leukemia, myelodysplasia (MDS), concurrent malignant disease, and significant cardiovascular disease (e.g. Grade III/IV congestive heart failure, atrial fibrillation, status post coronary artery bypass or stent placement) have not been established.

Paediatric population
The safety and efficacy of avatrombopag in children aged less than 18 years have not been established.
No data are available.

CYP2C9 loss-of-function polymorphisms
Avatrombopag exposure may increase in patients with CYP2C9*2 and CYP2C9*3 loss-of-function polymorphisms. Healthy subjects (n=2) who were homozygous for these mutations (poor metabolizers) had approximately 2-fold higher exposure compared to subjects with wild-type CYP2C9.

Method of administration

Optzuro is for oral use, and the tablets should be taken with food (see section 5.2).