Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
Laboratory Tests

Increased ALT, AST, and bilirubin
Increased ALT, AST, and bilirubin have been reported during treatment with tucatinib (see section 4.8).
ALT, AST, and total bilirubin should be monitored every three weeks or as clinically indicated. Based on the severity of the adverse reaction, treatment with tucatinib should be interrupted,then dose reduced or permanently discontinued (see section 4.2).

Increased creatinine without impaired renal function
Increase in serum creatinine (30% mean increase) has been observed due to inhibition of renal tubulartransport of creatinine without affecting glomerular function (see section 4.8). Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.


Diarrhoea

Diarrhoea, including severe events such as dehydration, hypotension, acute kidney injury and death, has been reported during treatment with tucatinib (see section 4.8). If diarrhoea occurs, antidiarrheals should be administered as clinically indicated. For Grade ≥3 diarrhoea, treatment with tucatinib should be interrupted, then dose reduced or permanently discontinued (see section 4.2). Prompt medical management should also be instituted in the event of persistence of concomitant Grade 2 diarrhoea with concomitant Grade ≥2 nausea and/or vomiting. Diagnostic tests should be performed as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhoea or diarrhoea of any grade with complicating features (dehydration, fever, neutropenia).

Embryo-foetal toxicity

Based on findings from animal studies and its mechanism of action, tucatinib may cause harmful effects to the foetus when administered to a pregnant woman. In animal reproduction studies, administration of tucatinib to pregnant rabbits during organogenesis caused foetal abnormalities in rabbits at maternal exposures similar to the clinical exposures at the recommended dose.
Pregnant women should be advised of the potential risk to a foetus. Women of childbearing potential should be advised to use effective contraception during and up to at least 1 week after the last dose of treatment (see section 4.6). Male patients with female partners of childbearing potential should also be advised to use an effective method of contraception during and up to at least 1 week after the last dose of treatment.

Sensitive CYP3A substrates

Tucatinib is a strong CYP3A inhibitor. Thus, tucatinib has the potential to interact with medicinal products that are metabolised by CYP3A, which may lead to increased plasma concentrations of the other product (see section 4.5). When tucatinib is co-administered with other medicinal products, the SmPC for the other product should be consulted for the recommendations regarding co-administration with CYP3A inhibitors. Concomitant treatment of tucatinib with CYP3A substrates when minimal concentration changes may lead to serious or life–threatening adverse reactions should be avoided. If concomitant use is unavoidable, the CYP3A substrate dosage should be reduced in accordance with the concomitant medicinal product SmPC.

P-gp substrates

Concomitant use of tucatinib with a P-gp substrate increased the plasma concentrations of P-gp substrate, which may increase the toxicity associated with a P-gp substrate. Dose reduction of P-gp substrates (including sensitive intestinal substrate such as dabigatran) should be considered in accordance with the concomitant medicine SmPC and P-gp substrates should be administered with caution when minimal concentration changes may lead to serious or life-threatening toxicities.

Strong CYP3A/moderate CYP2C8 inducers

Concomitant use of tucatinib with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib concentrations, which may reduce tucatinib activity. Concomitant use with a strong CYP3A inducer or moderate CYP2C8 inducer should be avoided.

Strong/moderate CYP2C8 inhibitors

Concomitant use of tucatinib with a strong CYP2C8 inhibitor increased tucatinib concentrations, which may increase the risk of tucatinib toxicity. Concomitant use with strong CYP2C8 inhibitors should be avoided (see section 4.2).
There are no clinical data on the impact of concomitant use of moderate CYP2C8 inhibitors on tucatinib concentrations. Monitoring for tucatinib toxicity should be increased with moderate CYP2C8 inhibitors.


Information about excipients

This medicinal product contains 55.3 mg sodium per 300 mg dose. This is equivalent to 2.75% of the recommended maximum daily dietary intake of sodium for an adult.

This medicinal product contains 60.6 mg potassium per 300 mg dose. This should be taken into consideration for patients who have impaired kidney function or are on a controlled potassium diet (diet with low potassium content).

Effects on Driving

4.7       Effects on ability to drive and use machines

TUKYSA has no or negligible influence on the ability to drive and use machines. The clinical status of the patient should be considered when assessing the patient’s ability to perform tasks that require judgment, motor, or cognitive skills.