Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Seagen B.V., Evert van de Beekstraat 1-104, 1118CL Schiphol, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Increased ALT, AST, and bilirubin have been reported during treatment with tucatinib (see section 4.8). ALT, AST, and 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).
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 GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.
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). 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).
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.
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.
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.
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.
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.
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).
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.
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).
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).
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.
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.
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 the toxicity associated with a CYP3A substrate. Concomitant use of tucatinib with CYP3A substrates, when minimal concentration changes may lead to serious or life-threatening toxicities, should be avoided. If concomitant use is unavoidable, the CYP3A substrate dosage should be decreased in accordance with the concomitant medicinal product SmPC.
A clinical drug interaction study found that co-administration of tucatinib with digoxin (a sensitive P-gp substrate) resulted in an increase in digoxin concentrations (2.4-fold Cmax (90% CI: 1.9, 2.9) and 1.5-fold AUC (90% CI: 1.3, 1.7)). Concomitant use of tucatinib with a P-gp substrate may increase the plasma concentrations of the P-gp substrate, which may increase the toxicity associated with the 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 (see section 4.4).
A clinical drug interaction study found that co-administration of tucatinib with repaglinide (a CYP2C8 substrate) resulted in an increase in repaglinide concentrations (1.7-fold Cmax (90% CI: 1.4, 2.1) and 1.7-fold AUC (90% CI: 1.5, 1.9)). No dose adjustment is required.
A clinical drug interaction study found that co-administration of tucatinib with metformin (a MATE1/2-K substrate) resulted in an increase in metformin concentrations (1.1-fold Cmax (90% CI: 1.0, 1.2) and 1.4-fold AUC (90% CI: 1.2, 1.5)). Tucatinib reduced the renal clearance of metformin without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C. No dose adjustment is required.
Based on clinical drug interaction studies conducted with tucatinib, no drug interactions were observed when tucatinib is combined with tolbutamide (a sensitive CYP2C9 substrate). No dose adjustment is required.
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.
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.
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.
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).
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.
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%).
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).
Table 4. Adverse reactions:
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Respiratory, thoracic and mediastinal disorders | Very common | Epistaxis |
| Gastrointestinal disorders | Very common | Diarrhoea, Nausea, Vomiting, Stomatitis1 |
| Skin and subcutaneous tissue disorders | Very common | Rash2 |
| Musculoskeletal and connective tissue disorders | Very common | Arthralgia |
| 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-papular, rash, dermatitis acneiform, erythema, rash macular, rash papular, rash pustular, rash pruritic, rash erythematous, skin exfoliation, urticaria, dermatitis allergic, palmar erythema, plantar erythema and skin toxicity.
3 Blood bilirubin increased also includes hyperbilirubinemia.
In HER2CLIMB, increased ALT, AST or bilirubin occurred in 41% of patients treated with tucatinib in combination with trastuzumab and capecitabine. Grade 3 and above events occurred in 9% of patients. Increased ALT, AST or bilirubin led to dose reduction in 9% of patients and treatment discontinuation in 1.5% of patients. The median time to onset of any grade increased ALT, AST, or bilirubin was 37 days; 84% of events resolved, with a median time to resolution of 22 days. Monitoring and dose modification (including discontinuation) should be considered (see section 4.4).
In HER2CLIMB, diarrhoea occurred in 82% of patients treated with tucatinib in combination with trastuzumab and capecitabine. Grade 3 and above diarrhoea events occurred in 13% of patients. Two patients who developed Grade 4 diarrhoea subsequently died, with diarrhoea as a contributor to death. Diarrhoea led to dose reduction in 6% of the patients and treatment discontinuation in 1% of the patients. The median time to onset of any grade diarrhoea was 12 days; 81% of diarrhoea events resolved, with a median time to resolution of 8 days. Prophylactic use of antidiarrheals was not required. Antidiarrheal medicinal products were used in less than half of the treatment cycles where diarrhoea events were reported. The median duration of antidiarrheal use was 3 days per cycle (see section 4.4).
Increase in serum creatinine has been observed in patients treated with tucatinib due to inhibition of renal tubular transport of creatinine without affecting glomerular function. In clinical studies, increases in serum creatinine (30% mean increase) occurred within the first cycle of tucatinib, remained elevated but stable throughout treatment and were reversible upon treatment discontinuation.
In the HER2CLIMB study, 82 patients who received tucatinib were ≥65 years, of whom 8 patients were ≥75 years. The incidence of serious adverse reactions was 34% in patients ≥65 years compared to 28% in patients <65 years. There were too few patients ≥75 years to assess differences in safety.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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