Tucatinib

concentrations, which may increase the risk of tucatinib toxicity. Concomitant use with strong CYP2C8 inhibitors should be avoided.

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.

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. 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.

For patients with severe hepatic impairment (Child-Pugh C), a reduced starting dose of 200 mg orally twice daily is recommended.

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.

There are no data from the use of tucatinib in pregnant women. Studies in animals have shown reproductive toxicity. Tucatinib 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 tucatinib. Breast-feeding may be resumed 1 week after treatment.

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.

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.

Tucatinib 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.

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 tucatinib 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 tucatinib 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 tucatinib in 431 patients with locally advanced unresectable or metastatic HER2-positive breast cancer who received tucatinib in combination with trastuzumab and capecitabine across two studies, HER2CLIMB and ONT-380-005 (see section 5.1). The median duration of exposure to tucatinib 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).

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.

Description of selected adverse reactions

Increased ALT, AST, or bilirubin

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.

Diarrhoea

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.

Increased creatinine without impaired renal function

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.

Special populations

Elderly

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.