Adverse reactions : תופעות לוואי

4.8       Undesirable effects

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).


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-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 (see section 4.4).

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 (see section 4.4).

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.

Reporting of suspected adverse reactions
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: /https://sideeffects.health.gov.il