Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden
Doptelet is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure.
Doptelet is indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).
Treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases. Doptelet 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.
Obtain a platelet count prior to the administration of Doptelet 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 |
Due to limited information, avatrombopag should not be taken for more than 5 days.
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.
Use the lowest dose of Doptelet needed to achieve and maintain a platelet count ≥ 50 × 109/L as necessary to reduce the risk for bleeding. Do not use avatrombopag to normalise platelet counts. In clinical studies, platelet counts generally increased within 1 week after starting avatrombopag and decreased within 1 to 2 weeks after discontinuation.
The recommended starting dose of Doptelet is 20 mg (1 tablet) once daily with food.
After initiating therapy, assess platelet counts at least once weekly until a stable platelet count ≥50 × 109/L and ≤150 × 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 × 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 |
|---|---|
| <50 after at least 2 weeks of avatrombopag treatment | • Increase One Dose Level per Table 3. • Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments. |
| >150 and ≤250 | • Decrease One Dose Level per Table 3. • Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments. |
| >250 | • Stop avatrombopag. • Increase platelet monitoring to twice weekly. • When platelet count is less than 100 × 109/L, decrease One Dose Level per Table 3 and reinitiate therapy. |
| <50 after 4 weeks of avatrombopag 40 mg once daily | • Discontinue avatrombopag. |
| >250 after 2 weeks of avatrombopag 20 mg weekly | • Discontinue avatrombopag. |
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 medication 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 medication should be reduced.
Discontinue avatrombopag if the platelet count does not increase to ≥50 × 109/L after 4 weeks of dosing at the maximum dose of 40 mg once daily. Discontinue Doptelet if the platelet count is greater than 250 × 109/L after 2 weeks of dosing at 20 mg once weekly.
The recommended starting doses of avatrombopag in patients with chronic immune thrombocytopenia receiving concomitant medications are summarised in Table 4.
Table 4. Avatrombopag recommended starting dose for patients with primary chronic immune thrombocytopenia based on concomitant medications:
| Concomitant medications | Recommended starting dose |
|---|---|
| Moderate or strong dual inhibitors of CYP2C9 and CYP3A4/5, or of CYP2C9 alone (e.g., fluconazole) | 20 mg (1 tablet) three times a week |
| Moderate or strong dual inducers of CYP2C9 and CYP3A4/5, or of CYP2C9 alone (e.g., rifampicin, enzalutamide) | 40 mg (2 tablets) once daily |
No dose adjustment is required for patients aged 65 years and older (see section 5.2).
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).
No dosage 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 dosage 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).
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.
The safety and efficacy of avatrombopag in children aged less than 18 years have not been established. No data are available.
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.
Doptelet is for oral use, and the tablets should be taken with food (see section 5.2).
There is no specific antidote for overdose with avatrombopag. Should overdose occur or be suspected, Doptelet dosing should be stopped and platelet count should be carefully monitored since avatrombopag increases platelet count in a dose-dependent fashion.
5 years.
This medicinal product does not require any special storage conditions.
Blister (polyamide and polyvinyl chloride-laminated aluminium film with push-through aluminium and polyethylene terephthalate foil) containing either 10 or 15 film-coated tablets. Each carton contains one blister of 10 or 15 film-coated tablets or two blisters of 15 film-coated tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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