Posology : מינונים

4.2   Posology and method of administration
Treatment with TUKYSA should be initiated and supervised by a physician experienced in the administration of anti–cancer medicinal products.
Posology

The recommended dose is 300 mg tucatinib (two 150 mg tablets) taken twice daily continuously in combination with trastuzumab and capecitabine, at doses described in table 1. Refer to the summary of product characteristics (SmPC) for co-administered trastuzumab and capecitabine for additional information. The treatment components can be administered in any order.

Table 1: Recommended dosing

Timing relative to
Treatment                             Dose                       Treatment days                  food intake 300 mg orally                                                    With or without a Tucatinib                           twice daily                       Continuously                   meal 1000 mg/m2 orally                 Days 1 to 14 every             Within 30 minutes Capecitabine twice daily                          21 days                     after a meal Trastuzumab
Intravenous dosing
Initial dose                   8 mg/kg intravenously             Day 1 Subsequent doses               6 mg/kg intravenously             Every 21 days                  Not applicable OR
Subcutaneous dosing               600 mg subcutaneously             Every 21 days 
Treatment with TUKYSA should be continued until disease progression or unacceptable toxicity.

Missed dose
In the case of a missed dose, the patient should take their next dose at the regularly scheduled time.
Dose modification
The recommended tucatinib dose modifications for patients with adverse reactions (see section 4.8) are provided in Tables 2 and 3. Refer to the SmPC for co-administered trastuzumab and capecitabine for dose modifications for toxicities suspected to be caused by those therapies.

Table 2: Recommended tucatinib dose reductions for adverse reactions
Dose level                                                   Tucatinib dose Recommended starting dose                                    300 mg twice daily First dose reduction                                         250 mg twice daily Second dose reduction                                        200 mg twice daily Third dose reduction                                         150 mg twice daily1 1. TUKYSA should be permanently discontinued in patients unable to tolerate 150 mg orally twice daily.




Table 3: Recommended tucatinib dose modifications for adverse reactions 
Adverse
Severity1                                   Tucatinib dosage modification Reaction
Diarrhoea              Grade 1 and 2                               No dose modification is required.


Grade 3 without anti-diarrheal              Initiate or intensify appropriate medical treatment                                   therapy. Interrupt tucatinib until recovery to
≤ Grade 1, then resume tucatinib at the same dose level.
Grade 3 with anti-diarrheal                 Initiate or intensify appropriate medical treatment                                   therapy. Interrupt tucatinib until recovery to
≤ Grade 1, then resume tucatinib at the next lower dose level.
Grade 4                                     Permanently discontinue tucatinib.
Increased ALT,         Grade 1 bilirubin (> ULN to 1.5 x           No dose modification is required.
AST or total           ULN) bilirubin2
Grade 2 bilirubin (> 1.5 to 3 ×             Interrupt tucatinib until recovery to ≤ Grade 1, ULN)                                        then resume tucatinib at the same dose level.



Grade 3 ALT or AST (> 5 to 20 ×             Interrupt tucatinib until recovery to ≤ Grade ULN)                                        1, then resume tucatinib at the next lower doselevel.
OR
Grade 3 bilirubin (> 3 to 10 ×
ULN)
Grade 4 ALT or AST (> 20 ×                  Permanently discontinue tucatinib.
ULN)
OR
Grade 4 bilirubin (> 10 × ULN)
ALT or AST > 3 × ULN                        Permanently discontinue tucatinib.
AND
Bilirubin > 2 × ULN
Other adverse          Grade 1 and 2                               No dose modification is required.
reactions
Grade 3                                     Interrupt tucatinib until recovery to ≤ Grade 1, then resume tucatinib at the next lower doselevel.
Grade 4                                     Permanently discontinue tucatinib.
1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse EventsVersion 4.03
2. Abbreviations: ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase

Co-administration with CYP2C8 inhibitors
Concomitant use with strong CYP2C8 inhibitors should be avoided. If coadministration with a strongCYP2C8 inhibitor cannot be avoided, the starting tucatinib dose should be reduced to 100 mg orally twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, the tucatinib dose that was taken prior to initiating the inhibitor should be resumed (see section 4.4 and section 4.5). Monitoring for TUKYSA toxicity should be increased when administered with moderateCYP2C8 inhibitors.


Special populations
Elderly
No dose adjustment is required in patients aged ≥ 65 years (see section 5.2). Tucatinib has not been investigated in patients above the age of 80 years.

Renal impairment
No dose adjustment is required in patients with mild, moderate, or severe renal impairment (seesection 5.2).

Hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2).For patients with severe hepatic impairment (Child-Pugh C), a reduced starting dose of 200 mg orally twice daily is recommended.

Paediatric population
The safety and efficacy of TUKYSA in paediatric patients have not been established. No data are available.


Method of administration
TUKYSA is for oral use. The tablets should be swallowed whole.
No information is available regarding crushing, splitting, or chewing of tablets.
TUKYSA should be taken approximately 12 hours apart, at the same time every day, with or without a meal. TUKYSA may be taken at the same time with capecitabine.