Tucatinib (Tukysa®) reimbursed as of October 2023

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See SmPC for how to report adverse reactions. NAME OF THE MEDICINAL PRODUCT TUKYSA 50 mg / 150 mg film‑coated tablets (tablets). QUALITATIVE AND QUANTITATIVE COMPOSITION TUKYSA 50mg film‑coated tablets Each film-coated tablet contains 50 mg of tucatinib. TUKYSA 150 mg film‑coated tablets Each film-coated tablet contains 150 mg of tucatinib. Excipients with known effect Each 150 mg film‑coated tablet contains 27.64 mg of sodium and 30.29 mg of potassium. A 300 mg dose of TUKYSA contains 55.3 mg of sodium and 60.6 mg of potassium. For the full list of excipients, see section SPI. PHARMACEUTICAL FORMFilm-coated tablet (tablet). TUKYSA 50 mg film‑coated tablets Round, yellow, film-coated tablet, debossed with “TUC” on one side and “50” on the other side. The 50 mg tablet has a diameter of approximately 8 mm. TUKYSA 150 mg film‑coated tablets Oval‑shaped, yellow, film-coated tablet, debossed with “TUC” on one side and “150” on the other side. The 150 mg tablet is approximately 17 mm in length and 7 mm in width. THERAPEUTIC INDICATIONS 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. POSOLOGY AND METHOD OF ADMINISTRATION Treatment with TUKYSA should be initiated and supervised by a physician experienced in the administration of anti–cancer medicinal products. Posology: The recommended dose is 300 mg tucatinib (two 150 mg tablets) taken twice daily continuously in combination with trastuzumab and capecitabine, at doses described below. Refer to the summary of product characteristics (SmPC) for co-administered trastuzumab and capecitabine for additional information. The treatment components can be administered in any order. Recommended dosing: Tucatinib 300 mg orally, twice daily, continuously, with or without a meal. Capecitabine 1000 mg/m2 orally, twice daily, days 1 to 14 every 21 days, within 30 minutes after a meal. Trastuzumab intravenous dosing, initial dose 8 mg/kg intravenously, day 1. Subsequent doses 6 mg/kg intravenously, every 21 days. Subcutaneous dosing 600 mg subcutaneously, every 21 days. Treatment with TUKYSA should be continued until disease progression or unacceptable toxicity. Missed dose:In the case of a missed dose, the patient should take their next dose at the regularly scheduled time. Dose modification: Refer to the SmPC for co‑administered trastuzumab and capecitabine for dose modifications for toxicities suspected to be caused by those therapies. Recommended tucatinib dose reductions for adverse reactions: Recommended starting dose 300 mg twice daily. First dose reduction 250 mg twice daily. Second dose reduction 200 mg twice daily. Third dose reduction 150 mg twice daily (TUKYSA should be permanently discontinued in patients unable to tolerate 150 mg orally twice daily). Recommended tucatinib dose reductions for adverse reactions: (Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03): Diarrhoea: Grade 1 and 2: No dose modification is required. Grade 3 without anti-diarrheal treatment: Initiate or intensify appropriate medical therapy. Interrupt tucatinib until recovery to ≤ Grade 1, then resume tucatinib at the same dose level. Grade 3 with anti-diarrheal treatment: Initiate or intensify appropriate medical therapy. Interrupt tucatinib until recovery to ≤ Grade 1, then resume tucatinib at the next lower dose level. Grade 4: Permanently discontinue tucatinib. Increased ALT, AST or total bilirubin (abbreviations: ULN =  upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase). Grade 1 bilirubin (> ULN to 1.5 x ULN): No dose modification is required. Grade 2 bilirubin (> 1.5 to 3 × ULN): Interrupt tucatinib until recovery to ≤ Grade 1, then resume tucatinib at the same dose level. Grade 3 ALT or AST (> 5 to 20 × ULN) OR Grade 3 bilirubin (> 3 to 10 × ULN):  Interrupt tucatinib until recovery to ≤ Grade 1, then resume tucatinib at the next lower dose level. Grade 4 ALT or AST (> 20 × ULN) OR Grade 4 bilirubin (> 10 × ULN): Permanently discontinue tucatinib. ALT or AST > 3 × ULN AND Bilirubin > 2 × ULN: Permanently discontinue tucatinib. Other adverse reactions: Grade 1 and 2: No dose modification is required. Grade 3: Interrupt tucatinib until recovery to ≤ Grade 1, then resume tucatinib at the next lower dose level. Grade 4: Permanently discontinue tucatinib. Co-administration with CYP2C8 inhibitors: Concomitant use with strong CYP2C8 inhibitors should be avoided. If coadministration with a strong CYP2C8 inhibitor cannot be avoided, the starting tucatinib dose should be reduced to 100 mg orally twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, the tucatinib dose that was taken prior to initiating the inhibitor should be resumed (see SPI). Monitoring for TUKYSA toxicity should be increased when administered with moderate CYP2C8 inhibitors. Special populations: Elderly:  No dose adjustment is required in patients aged ≥ 65 years (see section 5.2). Tucatinib has not been investigated in patients above the age of 80 years. Renal impairment: No dose adjustment is required in patients with mild, moderate, or severe renal impairment (see SPI). Hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment (see SPI). For patients with severe hepatic impairment (Child-Pugh C), a reduced starting dose of 200 mg orally twice daily is recommended. Paediatric population: The safety and efficacy of TUKYSA in paediatric patients have not been established. No data are available. Method of administration: TUKYSA is for oral use. The tablets should be swallowed whole and should not be chewed, crushed, or split prior to swallowing (see SPI). TUKYSA should be taken approximately 12 hours apart, at the same time every day, with or without a meal. TUKYSA may be taken at the same time with capecitabine. CONTRAINDICATIONS Hypersensitivity to the active substance or to any of the excipients. 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 SPI). 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). Respiratory, thoracic and mediastinal disorders: Very common: Epistaxis. Gastrointestinal disorders: Very common: Diarrhoea, nausea, vomiting, stomatitis (Stomatitis includes stomatitis, oropharyngeal pain, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysaesthesia, tongue ulceration, aphthous ulcer). Skin and subcutaneous tissue disorders: Very common: Rash (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). Musculoskeletal and connective tissue disorders: Very common: Arthralgia. Investigations: Very common: AST increase, ALT increase, blood bilirubin increased (Blood bilirubin increased also includes hyperbilirubinemia), weight decrease. 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 SPI). 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 SPI). 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. Healthcare professionals are asked to report any suspected adverse reactions in Belgium via Agence fédérale des médicaments et des produits de santé, Division Vigilance, Avenue Galilée 5/03, 1210 BRUXELLES / Boîte Postale 97, B-1000 BRUXELLES Madou. Site internet: www.notifieruneffetindesirable.be – mail to: e-mail: adr@afmps.be and in Luxembourg via Centre Régional de Pharmacovigilance de Nancy, Bâtiment de Biologie Moléculaire et de Biopathologie (BBB), CHRU de Nancy – Hôpitaux de Brabois, Rue du Morvan, 54 511 VANDOEUVRE LES NANCY CEDEX Phone: (+33) 3 83 65 60 85 / 87, e-mail: crpv@chru-nancy.fr or Direction de la Santé, Division de la Pharmacie et des Médicaments, 20, rue de Bitbourg, L-1273 Luxembourg-Hamm, Phone: (+352) 2478 5592, e-mail: pharmacovigilance@ms.etat.lu Lien pour le formulaire: https://guichet.public.lu/fr/entreprises/sectoriel/sante/medecins/notification-effets-indesirables-medicaments.html. MARKETING AUTHORISATION HOLDER Seagen B.V., Evert van de Beekstraat 1 104, 1118CL Schiphol, The Netherlands. MARKETING AUTHORISATION NUMBER TUKYSA 50 mg tablets: EU/1/20/1526/001, TUKYSA 150 mg tablets: EU/1/20/1526/002. delivery On medical prescription. DATE OF REVISION OF THE TEXT 02/2023 BE-TUP-21-102-MT  04/2023