Tukysa · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-099380 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most commonly reported Grade 3 and 4 adverse reactions (≥ 5%) during treatment are diarrhoea (13%), ALT increased (6%) and AST increased (5%). Serious adverse reactions occurred in 29% of patients treated with tucatinib, and include diarrhoea (4%), vomiting (3%), and nausea (2%). Adverse reactions leading to discontinuation of TUKYSA occurred in 6% of patients; the most common adverse reactions leading to discontinuation were diarrhoea (1%) and ALT increased (1%). Adverse reactions leading to dose reduction of TUKYSA occurred in 23% of patients; the most common adverse reactions leading to dose reduction were diarrhoea (6%), ALT increased (5%), and AST increased (4%). Tabulated list of adverse reactions The data summarised in this section reflect exposure to TUKYSA in 431 patients with locally advanced unresectable or metastatic HER2-positive breast cancer who received TUKYSA in combination with trastuzumab and capecitabine across two studies, HER2CLIMB and ONT-380-005 (see section 5.1). The median duration of exposure to TUKYSA across these studies was 7.4 months (range, < 0.1, 43.6). The adverse reactions observed during treatment are listed in this section by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). 9 Table 4: Adverse reactions System organ class Frequency Adverse reaction Respiratory, thoracic and Very common Epistaxis mediastinal disorders Gastrointestinal disorders Very common Diarrhoea, Nausea, Vomiting, Stomatitis1 Skin and subcutaneous tissue Very common Rash2 disorders Musculoskeletal and connective Very common Arthralgia tissue disorders Investigations Very common AST increase, ALT increase, Blood bilirubin increased3, weight decrease 1.Stomatitis includes stomatitis, oropharyngeal pain, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysaesthesia, tongue ulceration, aphthous ulcer 2.Rash includes rash maculo-papul

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HOS-099376 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-099375 · has-indication-information · PDF-Seite 2

TUKYSA is indicated in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least 2 prior anti-HER2 treatment regimens.

HOS-099378 · has-interaction-information · PDF-Seite 7

Tucatinib is primarily metabolised by CYP2C8. Tucatinib is a metabolism-based inactivator of CYP3A and inhibits renal transporters of metformin and creatinine. Tucatinib is a substrate of P–gp. Effects of other medicinal products on tucatinib CYP3A/CYP2C8 inducers A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib with rifampicin (a strong CYP3A and moderate CYP2C8 inducer) resulted in a reduction in tucatinib concentrations (0.6-fold Cmax (90% CI: 0.5, 0.8) and 0.5-fold AUC (90% CI: 0.4, 0.6)). Co-administration of tucatinib with strong CYP3A or moderate CYP2C8 inducers such as rifampicin, phenytoin, St. John's wort, or carbamazepine should be avoided as this may result in decreased activity of tucatinib (see section 4.4). CYP2C8 inhibitors A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib with gemfibrozil (a strong CYP2C8 inhibitor) resulted in an increase in tucatinib concentrations (1.6-fold Cmax (90% CI: 1.5, 1.8) and 3.0-fold AUC (90% CI: 2.7, 3.5)). Co-administration of tucatinib with strong CYP2C8 inhibitors such as gemfibrozil should be avoided as this may result in increased risk of tucatinib toxicity (see section 4.4). CYP3A inhibitors A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib with itraconazole (a strong CYP3A inhibitor) resulted in an increase in tucatinib concentrations (1.3-fold Cmax (90% CI: 1.2, 1.4) and 1.3-fold AUC (90% CI: 1.3, 1.4)). No dose adjustment is required. Proton pump inhibitors Based on clinical drug interaction studies conducted with tucatinib, no drug interactions were observed when tucatinib is combined with omeprazole (a proton pump inhibitor). No dose adjustment is required. Effects of tucatinib on other medicinal products CYP3A substrates Tucatinib is a strong CYP3A inhibitor. A clinical drug interaction study found that co-administration of tucatinib with midazolam (a sensitive CYP3A substrate) resulted in an increase in midazolam concentrations (3.0-fold Cmax (90% CI: 2.6, 3.4) and 5.7-fold AUC (90% CI: 5.0, 6.5)). Co-administration of tucatinib with sensitive CYP3A substrates such as alfentanil, avanafil, buspirone, darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, and vardenafil may increase their systemic exposures which may increase

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HOS-099379 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception in males and females Based on findings in animals, tucatinib may cause harmful pharmacological effects when administered to women during pregnancy and/or on the foetus/newborn child. Women of childbearing potential should be advised to avoid becoming pregnant and to use effective contraception during and up to at least 1 week after treatment. Male patients with female partners of childbearing potential should also be advised to use effective contraception during and up to at least 1 week after treatment (see section 4.4). Please also refer to section 4.6 of the prescribing information for trastuzumab and capecitabine. Pregnancy There are no data from the use of tucatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). TUKYSA should not be used during pregnancy unless the clinical condition of the woman requires treatment with tucatinib. The pregnancy status of women of childbearing potential should be verified prior to initiating treatment with tucatinib. If the patient becomes pregnant during treatment, the potential hazard to the foetus/newborn child must be explained to the patient. Breast-feeding It is unknown whether tucatinib/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with TUKYSA. Breast-feeding may be resumed 1 week after treatment. 8 Fertility No fertility studies in men or women have been conducted. Based on findings from animal studies, tucatinib may impair fertility in females of reproductive potential (see section 5.3).

HOS-099377 · has-warning-information · PDF-Seite 5

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 tubular transport of creatinine without affecting glomerular function (see section 4.8). Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (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 5 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 treatmen

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