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TUKYSA is a brand name for Tucatinib, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: TUKYSA (tucatinib) is indicated in combination with trastuzumab and capecitabine for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine,…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations TUKYSA tablets should be swallowed whole. Tablets should not be chewed, crushed, or split prior to swallowing. 2 Recommended Dose and Dosage Adjustment The recommended dose of TUKYSA is 300 mg (two 150 mg tablets) taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity (see Table 1).
For additional information on dosing and administration of the co- administered trastuzumab and capecitabine, consult the respective Product Monographs.
Table 1:
Recommended dosing Treatment Dose Treatment Days Timing Relative to Food Intake TUKYSA 300 mg orally twice daily Continuously Take with or without a meal Capecitabine 1000 mg/m2 orally twice daily Days 1 to 14 every 21 days Take within 30 minutes after a meal Trastuzumab Intravenous dosing Not applicable Initial dose 8 mg/kg intravenously Day 1 Subsequent doses 6 mg/kg intravenously Every 21 days OR Subcutaneous dosing 600 mg subcutaneously Every 21 days 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. TUKYSA® Product Monograph Page 6 of 34 Patients with Hepatic Impairment For patients with baseline severe hepatic impairment (Child-Pugh C), reduce the starting dose of TUKYSA to 200 mg orally twice daily (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
No starting dose adjustment is required in patients with baseline mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Patients with Renal Impairment TUKYSA in combination with capecitabine and trastuzumab cannot be used in patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
No starting dose adjustment is required in patients with baseline mild to moderate renal impairment (CrCL ≥ 30 mL/min) (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). Concomitant Use with Strong CYP2C8 Inhibitors Avoid concomitant use of strong CYP2C8 inhibitors with TUKYSA.
If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the TUKYSA starting dose to 100 mg twice daily and increase monitoring for tucatinib-related toxicity. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the TUKYSA dose taken prior to initiating the inhibitor (see DRUG INTERACTIONS).
1 Adverse Reaction Overview The data described in this section reflect exposure to TUKYSA in combination with trastuzumab and capecitabine from HER2CLIMB, a randomized, double-blind, placebo-controlled, active comparator, global trial in patients with locally advanced unresectable or metastatic HER2- positive breast cancer, who received at least one dose of study drug.
0) on the control arm. 7%), and treatment-related adverse events (85% vs 73%) than those treated with placebo. The most common treatment emergent adverse events in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
Serious adverse events occurred in 26% of patients treated with TUKYSA compared to 27% of patients treated with placebo + trastuzumab + capecitabine (control arm). The most common serious adverse events (≥2%) in patients treated with TUKYSA were diarrhea (4%), vomiting (2%), nausea (2%), abdominal pain (2%), and seizure (2%).
Fatal adverse events occurred in 2% of patients who received TUKYSA compared to 3% of patients on the control arm. Events leading to death in the TUKYSA arm included sudden death, sepsis, dehydration, and cardiogenic shock. Adverse events leading to treatment discontinuation of TUKYSA/placebo occurred in 6% of patients on the TUKYSA arm compared to 3% of patients in the control arm; the most common adverse events leading to treatment discontinuation of TUKYSA were diarrhea (1%) and ALT increased (1%).
Adverse events leading to dose reduction occurred in 21% of patients treated with TUKYSA compared to 11% of patients in the control arm; the most common adverse events leading to dose reduction of TUKYSA were diarrhea (6%), ALT increased (5%), and AST increased (4%).
2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
General Patients with brain metastases requiring immediate local therapy were excluded from the pivotal HER2CLIMB study. These patients should undergo local CNS directed therapy prior to being treated with TUKYSA, if appropriate (see CLINICAL TRIALS).
Driving and Operating Machinery Due caution should be exercised when driving or operating a vehicle or potentially dangerous Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Oral 50 mg tablets: round, convex, yellow, film- coated, debossed with “TUC” on one side and “50” on the other side.
150 mg tablets: oval- shaped, yellow, film- coated, debossed with “TUC” on one side and “150” on the other side. Tablet core Colloidal silicon dioxide Copovidone Crospovidone Potassium chloride Sodium bicarbonate Sodium chloride Magnesium stearate Microcrystalline cellulose Coating Polyvinyl alcohol Titanium dioxide Macrogol/polyethylene glycol Talc Yellow iron oxide non-irradiated TUKYSA® Product Monograph Page 9 of 34 machinery.
Gastrointestinal Diarrhea Diarrhea, including severe events, has been reported during treatment with TUKYSA in combination with trastuzumab and capecitabine (see ADVERSE REACTIONS). 5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death.
The median time to onset of the first episode of diarrhea was 12 days; 80% of diarrhea events resolved with a median time to resolution of 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients.
Prophylactic use of antidiarrheals was not mandated in the HER2CLIMB trial. If diarrhea occurs, administer antidiarrheals as clinically indicated. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA (see DOSAGE AND ADMINISTRATION) and refer to the trastuzumab and capecitabine Product Monographs for relevant safety information and dose modifications.
TUKYSA is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.
Refer to the Product Monographs of capecitabine and trastuzumab for further information on the contraindications of these drugs. TUKYSA® Product Monograph Page 5 of 34
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Pediatrics (<18 years of age) Health Canada has not authorized an indication for pediatric use. Geriatrics (≥ 65 years old) No dose adjustment is required in patients ≥ 65 years of age (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Dose Modifications for Adverse Reactions The recommended TUKYSA dose modifications for patients with adverse reactions are provided in Tables 2 to 3. Refer to the Product Monographs for co-administered trastuzumab and capecitabine for dose modifications for toxicities suspected to be caused by those therapies.
Table 2:
TUKYSA Dose Reduction Schedule Dose Level TUKYSA Dose 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 daily1 1. Permanently discontinue TUKYSA in patients unable to tolerate 150 mg twice daily.
TUKYSA® Product Monograph Page 7 of 34 Table 3:
TUKYSA Dose Modifications for Adverse Reactions Adverse Reaction1 Severity TUKYSA Dose Modification Diarrhea Grade 3 without anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level.
Grade 3 with anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level. Grade 4 Permanently discontinue TUKYSA. 5 – ≤ 3 x ULN) Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level.
Grade 3 elevation of ALT or AST (> 5 – ≤ 20 x ULN) OR Grade 3 elevation of bilirubin (> 3 ≤ 10 x ULN) Hold TUKYSA until severity ≤ Grade 1. Then resume TUKYSA at the next lower dose level. Grade 4 elevation of ALT or AST (> 20 x ULN) OR Grade 4 elevation of bilirubin (> 10 x ULN) Permanently discontinue TUKYSA.
ALT or AST > 3 x ULN AND Bilirubin > 2 x ULN Permanently discontinue TUKYSA. Other Adverse Reactions Grade 3 Hold TUKYSA until severity ≤ Grade 1. Then resume TUKYSA at the next lower dose level. Grade 4 Permanently discontinue TUKYSA.
ULN: upper limit of normal; ALT: alanine aminotransferase; AST: aspartate aminotransferase 1. 3 Missed Dose If a patient misses or vomits a dose, they should take their next dose at the regularly scheduled time.
Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Table 5 summarizes treatment emergent adverse events reported in patients in HER2CLIMB. 5) 0 (0) 1. Anemia includes anemia, hemoglobin decreased, and normocytic anemia 2.
Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysaethesia, tongue ulceration, apthous ulcer TUKYSA® Product Monograph Page 14 of 34 3.
Hepatotoxicity includes hyperbilirubinemia, blood bilirubin increased, bilirubin conjugated increased, alanine aminotransferase increased, transaminases increased, hepatotoxicity, aspartate aminotransferase increased, liver function test increased, liver injury, and hepatocellular injury 4.
Due to inhibition of renal tubular transport of creatinine without affecting glomerular function 5. Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy 6.
3 Less Common Clinical Trial Adverse Reactions Additional clinically important adverse events, regardless of relationship to TUKYSA, that occurred in <10% of patients treated with TUKYSA in combination with trastuzumab and capecitabine include: Cardiac disorders: cardiac failure, palpitations Gastrointestinal disorders: dysphagia, rectal hemorrhage General disorders and administration site conditions: chest discomfort, influenza-like illness, non-cardiac chest pain, peripheral swelling, pyrexia Infections and infestations: septic shock Investigations: glomerular filtration rate decreased, neutrophil count decreased, platelet count decreased Metabolism and nutrition disorders: […]
Perform diagnostic tests as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia). Stomatitis Stomatitis has been reported during treatment with TUKYSA in combination with trastuzumab and capecitabine.
5% with Grade 3. If stomatitis occurs, follow the dose modification guidelines for TUKYSA in Table 3 (see DOSAGE AND ADMINISTRATION) and refer to the trastuzumab and capecitabine Product Monographs for relevant safety information and dose modifications.
Hepatic/Biliary/Pancreatic Hepatotoxicity Hepatotoxicity, including severe hepatotoxicity, has been reported during treatment with TUKYSA. In HER2CLIMB, the median time to onset of any grade increased ALT, AST, or bilirubin was 36 days; 84% of events resolved, with a median time to resolution of 22 days.
5% had a bilirubin increase > 3 × ULN (Grade ≥3); 2% of patients had AST and/or ALT increased > 10 × ULN. 5% of patients. If hepatotoxicity occurs, based on its severity, interrupt dose, then dose reduce or permanently discontinue TUKYSA (see DOSAGE AND ADMINISTRATION).
Patients with known chronic liver disease, or carriers of hepatitis B or C were excluded from the pivotal study. 5 × ULN, or AST/ALT > 5 × ULN if liver metastases were present) were excluded from clinical trials with TUKYSA. Monitoring and Laboratory Tests TUKYSA® Product Monograph Page 10 of 34 Liver Function Monitoring Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every three weeks, and as clinically indicated.
Creatinine Increased Although not an adverse reaction, increased serum creatinine was observed in 14% of patients treated with TUKYSA 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 21 days of treatment with TUKYSA remained elevated but stable throughout treatment and were reversible upon treatment discontinuation.
Alternative markers such as BUN, cystatin C, or calculated GFR (if not based on creatinine), may be considered to determine whether renal function is impaired. Sexual Health Reproduction Pregnancy testing Verify the pregnancy status of female patients of reproductive potential prior to initiating TUKYSA (see Special Populations).
Contraception Advise female patients of reproductive potential of potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 week after the last dose (see Special Populations).
Advise male patients with female partners who are pregnant, possibly pregnant, or who could become pregnant to use effective barrier contraception during treatment with TUKYSA and for at least 1 week after the last dose of TUKYSA. Male patients are also advised not to donate or store semen during treatment and at least 1 month after the last dose of TUKYSA.
Fertility No fertility studies in women or men have been conducted. Based on findings from animal studies, TUKYSA may impair male and female fertility (see NON- CLINICAL TOXICOLOGY). Skin Palmar-plantar erthrodysesthesia syndrome Palmar-plantar erthrodysesthesia syndrome has been reported during treatment with TUKYSA in combination with trastuzumab and capecitabine.
In HER2CLIMB, 63% of patients who received TUKYSA experienced palmar-plantar erthrodysesthesia, including 13% with Grade 3. If […]