TUKYSA® Adverse Reactions

(tucatinib)

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Diarrhea [see Warnings and Precautions (5.1)]
  • Hepatotoxicity [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

HER2-Positive Metastatic Breast Cancer

The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB [see Clinical Studies (14)].  Patients received either TUKYSA 300 mg twice daily plus trastuzumab or a non-US approved trastuzumab product, and capecitabine (n=404) or placebo plus trastuzumab or a non-US approved trastuzumab product and capecitabine (n=197). The median duration of treatment was 5.8 months (range: 3 days, 2.9 years) for the TUKYSA arm.

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥ 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received TUKYSA. Adverse reactions leading to treatment discontinuation of TUKYSA in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%).

Adverse reactions leading to dose reduction occurred in 21% of patients who received TUKYSA. Adverse reactions leading to dose reduction of TUKYSA in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash.

Table 3 summarizes the adverse reactions in HER2CLIMB.

Table 3: Adverse Reactions (≥10%) in Patients Who Received TUKYSA and with a Difference Between Arms of ≥ 5% Compared to Placebo in HER2CLIMB (All Grades)
  1. Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysesthesia, tongue ulceration, and 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, skin toxicity, and dermatitis
  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. Anemia includes anemia, hemoglobin decreased, and normocytic anemia
  5. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
  6. Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy
Adverse ReactionTUKYSA + Trastuzumab +
Capecitabine
N = 404		Placebo + Trastuzumab +
Capecitabine
N = 197
All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%
Gastrointestinal disorders
Diarrhea 81 12 0.5 53 9 0
Nausea 58 3.7 0 44 3 0
Vomiting 36 3 0 25 3.6 0
Stomatitis1 32 2.5 0 21 0.5 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome 63 13 0 53 9 0
Rash2 20 0.7 0 15 0.5 0
Hepatobiliary disorders
Hepatotoxicity3 42 9 0.2 24 3.6 0
Metabolism and nutrition disorders
Decreased appetite 25 0.5 0 20 0 0
Blood and lymphatic system disorders
Anemia4 21 3.7 0 13 2.5 0
Musculoskeletal and connective tissue disorders
Arthralgia 15 0.5 0 4.6 0.5 0
Investigations
Creatinine increased5 14 0 0 1.5 0 0
Weight decreased 13 1 0 6 0.5 0
Nervous System Disorders
Peripheral neuropathy6 13 0.5 0 7 1 0
Respiratory, thoracic and mediastinal disorders
Epistaxis 12 0 0 5 0 0
Table 4: Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received TUKYSA and with a Difference of ≥5% Compared to Placebo in HER2CLIMB
  1. The denominator used to calculate the rate varied from 351 to 400 in the TUKYSA arm and 173 to 197 in the control arm based on the number of patients with a baseline value and at least one post-treatment value. Grading was based on NCI-CTCAE v.4.03 for laboratory abnormalities, except for increased creatinine which only includes patients with a creatinine increase based on the upper limit of normal definition for grade 1 events (NCI CTCAE v5.0).
  2. Laboratory criteria for Grade 1 is identical to laboratory criteria for Grade 2.
  3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function.
  4. There is no definition for Grade 2 in CTCAE v.4.03.
 

Laboratory Abnormality		TUKYSA + Trastuzumab
+ Capecitabine1		Placebo + Trastuzumab
+ Capecitabine1
All Grades
%		Grades ≥3
%		All Grades
%		Grades ≥
3%
Hematology
Decreased hemoglobin 59 3.3 51 1.5
Chemistry
Decreased phosphate 57 8 45 7
Increased bilirubin 47 1.5 30 3.1
Increased ALT 46 8 27 0.5
Increased AST 43 6 25 1
Decreased magnesium 40 0.8 25 0.5
Decreased potassium 2 36 6 31 5
Increased creatinine 3 33 0 6 0
Decreased sodium 4 28 2.5 23 2
Increased alkaline phosphatase 26 0.5 17 0

Increased Creatinine

The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

RAS Wild-Type, HER2-Positive Unresectable or Metastatic Colorectal Cancer

The safety of TUKYSA in combination with trastuzumab or a non-US approved trastuzumab product was evaluated in 86 patients enrolled in MOUNTAINEER with unresectable or metastatic colorectal cancer [see Clinical Studies (14.2)]. The median duration of exposure to TUKYSA was 6.9 months (range 0.7, 49.3).

Serious adverse reactions occurred in 22% of patients. Serious adverse reactions that occurred in ≥ 2% of patients were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%) and rectal perforation (2.3%).  

Permanent discontinuation of TUKYSA due to an adverse reaction occurred in 6% of patients. The adverse reaction which resulted in permanent discontinuation of TUKYSA in ≥2% of patients was increased ALT (2.3%). Dosage interruptions of TUKYSA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were increased ALT (3.5%) and diarrhea (3.5%). Dose reductions of TUKYSA due to an adverse reaction occurred in 9% of patients. Adverse reactions which required dose reductions in ≥2% of patients were increased ALT (2.3%) and diarrhea (2.3%).

The most common adverse reactions reported in ≥ 20% of patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities reported in ≥ 20% of patients were increased creatinine, increased glucose, increased ALT, decreased hemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.

Table 5 summarizes the adverse reactions in MOUNTAINEER.

Table 5: Adverse Reactions (≥10%) in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
*Includes 1 patient who only received trastuzumab.
1. Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper.
2. Rash includes acne, dermatitis acneiform, dermatitis contact, erythema, erythema multiforme, rash, rash macular, rash maculo-papular, rash papular, rash pustular, skin exfoliation, and urticaria,

Adverse Reaction		TUKYSA + Trastuzumab
N= 86*
All Grades%Grade 3%
Gastrointestinal disorders
Diarrhea 64 3.5
Nausea 35 0
Vomiting 16 0
Abdominal pain1 21 2.3
Constipation 14 1.2
General disorders
Fatigue 44 2.3
Pyrexia 20 0
Chills 19 1.2
Skin and subcutaneous disorders
Rash2 37 0
Injury, poisoning, and procedural complications
Infusion related reaction 21 0
Metabolism and nutrition disorders
Decreased appetite 19 0
Blood and lymphatic system disorders
Anemia 10 0
Vascular disorders

Hypertension 17 7
Musculoskeletal and connective tissue disorders
Back pain 17 2.3
Arthralgia 16 1.2
Myalgia 13 0
Respiratory, thoracic and mediastinal disorders
Cough 16 0
Dyspnea 14 0
Psychiatric disorders
Anxiety 10 0

Other adverse reactions (<10%) include epistaxis (7%), weight decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%), and stomatitis (1%).

Table 6: Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
1. Number of patients with both baseline and post-baseline results for each test
2. NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for all other laboratory parameters.
3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
Laboratory AbnormalityTUKYSA + Trastuzumab
N=851
All Grades%Grade 3%Grade 4%
Hematology
Decreased hemoglobin 46 3.5 0
Decreased lymphocytes 39 12 0
Decreased leukocytes 22 0 0
Decreased platelets 15 0 0
Chemistry
Increased creatinine2,3 58 0 0
Increased glucose 56 2.4 0
Increased ALT 46 2.4 2.4
Increased AST 33 2.4 3.5
Increased bilirubin 28 3.5 2.4
Increased alkaline phosphatase 25 1.2 0
Decreased albumin 24 1.2 0
Decreased sodium 20 6 0
Decreased potassium 16 1.2 0

Increased Creatinine

The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible in 87% of patients with values outside normal lab limits upon treatment completion.  Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

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Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Diarrhea [see Warnings and Precautions (5.1)]
  • Hepatotoxicity [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

HER2-Positive Metastatic Breast Cancer

The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB [see Clinical Studies (14)].  Patients received either TUKYSA 300 mg twice daily plus trastuzumab or a non-US approved trastuzumab product, and capecitabine (n=404) or placebo plus trastuzumab or a non-US approved trastuzumab product and capecitabine (n=197). The median duration of treatment was 5.8 months (range: 3 days, 2.9 years) for the TUKYSA arm.

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥ 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received TUKYSA. Adverse reactions leading to treatment discontinuation of TUKYSA in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%).

Adverse reactions leading to dose reduction occurred in 21% of patients who received TUKYSA. Adverse reactions leading to dose reduction of TUKYSA in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash.

Table 3 summarizes the adverse reactions in HER2CLIMB.

Table 3: Adverse Reactions (≥10%) in Patients Who Received TUKYSA and with a Difference Between Arms of ≥ 5% Compared to Placebo in HER2CLIMB (All Grades)
  1. Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysesthesia, tongue ulceration, and 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, skin toxicity, and dermatitis
  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. Anemia includes anemia, hemoglobin decreased, and normocytic anemia
  5. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
  6. Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy
Adverse ReactionTUKYSA + Trastuzumab +
Capecitabine
N = 404		Placebo + Trastuzumab +
Capecitabine
N = 197
All Grades%Grade 3%Grade 4%All Grades%Grade 3%Grade 4%
Gastrointestinal disorders
Diarrhea 81 12 0.5 53 9 0
Nausea 58 3.7 0 44 3 0
Vomiting 36 3 0 25 3.6 0
Stomatitis1 32 2.5 0 21 0.5 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome 63 13 0 53 9 0
Rash2 20 0.7 0 15 0.5 0
Hepatobiliary disorders
Hepatotoxicity3 42 9 0.2 24 3.6 0
Metabolism and nutrition disorders
Decreased appetite 25 0.5 0 20 0 0
Blood and lymphatic system disorders
Anemia4 21 3.7 0 13 2.5 0
Musculoskeletal and connective tissue disorders
Arthralgia 15 0.5 0 4.6 0.5 0
Investigations
Creatinine increased5 14 0 0 1.5 0 0
Weight decreased 13 1 0 6 0.5 0
Nervous System Disorders
Peripheral neuropathy6 13 0.5 0 7 1 0
Respiratory, thoracic and mediastinal disorders
Epistaxis 12 0 0 5 0 0
Table 4: Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received TUKYSA and with a Difference of ≥5% Compared to Placebo in HER2CLIMB
  1. The denominator used to calculate the rate varied from 351 to 400 in the TUKYSA arm and 173 to 197 in the control arm based on the number of patients with a baseline value and at least one post-treatment value. Grading was based on NCI-CTCAE v.4.03 for laboratory abnormalities, except for increased creatinine which only includes patients with a creatinine increase based on the upper limit of normal definition for grade 1 events (NCI CTCAE v5.0).
  2. Laboratory criteria for Grade 1 is identical to laboratory criteria for Grade 2.
  3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function.
  4. There is no definition for Grade 2 in CTCAE v.4.03.
 

Laboratory Abnormality		TUKYSA + Trastuzumab
+ Capecitabine1		Placebo + Trastuzumab
+ Capecitabine1
All Grades
%		Grades ≥3
%		All Grades
%		Grades ≥
3%
Hematology
Decreased hemoglobin 59 3.3 51 1.5
Chemistry
Decreased phosphate 57 8 45 7
Increased bilirubin 47 1.5 30 3.1
Increased ALT 46 8 27 0.5
Increased AST 43 6 25 1
Decreased magnesium 40 0.8 25 0.5
Decreased potassium 2 36 6 31 5
Increased creatinine 3 33 0 6 0
Decreased sodium 4 28 2.5 23 2
Increased alkaline phosphatase 26 0.5 17 0

Increased Creatinine

The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

RAS Wild-Type, HER2-Positive Unresectable or Metastatic Colorectal Cancer

The safety of TUKYSA in combination with trastuzumab or a non-US approved trastuzumab product was evaluated in 86 patients enrolled in MOUNTAINEER with unresectable or metastatic colorectal cancer [see Clinical Studies (14.2)]. The median duration of exposure to TUKYSA was 6.9 months (range 0.7, 49.3).

Serious adverse reactions occurred in 22% of patients. Serious adverse reactions that occurred in ≥ 2% of patients were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%) and rectal perforation (2.3%).  

Permanent discontinuation of TUKYSA due to an adverse reaction occurred in 6% of patients. The adverse reaction which resulted in permanent discontinuation of TUKYSA in ≥2% of patients was increased ALT (2.3%). Dosage interruptions of TUKYSA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were increased ALT (3.5%) and diarrhea (3.5%). Dose reductions of TUKYSA due to an adverse reaction occurred in 9% of patients. Adverse reactions which required dose reductions in ≥2% of patients were increased ALT (2.3%) and diarrhea (2.3%).

The most common adverse reactions reported in ≥ 20% of patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities reported in ≥ 20% of patients were increased creatinine, increased glucose, increased ALT, decreased hemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.

Table 5 summarizes the adverse reactions in MOUNTAINEER.

Table 5: Adverse Reactions (≥10%) in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
*Includes 1 patient who only received trastuzumab.
1. Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper.
2. Rash includes acne, dermatitis acneiform, dermatitis contact, erythema, erythema multiforme, rash, rash macular, rash maculo-papular, rash papular, rash pustular, skin exfoliation, and urticaria,

Adverse Reaction		TUKYSA + Trastuzumab
N= 86*
All Grades%Grade 3%
Gastrointestinal disorders
Diarrhea 64 3.5
Nausea 35 0
Vomiting 16 0
Abdominal pain1 21 2.3
Constipation 14 1.2
General disorders
Fatigue 44 2.3
Pyrexia 20 0
Chills 19 1.2
Skin and subcutaneous disorders
Rash2 37 0
Injury, poisoning, and procedural complications
Infusion related reaction 21 0
Metabolism and nutrition disorders
Decreased appetite 19 0
Blood and lymphatic system disorders
Anemia 10 0
Vascular disorders

Hypertension 17 7
Musculoskeletal and connective tissue disorders
Back pain 17 2.3
Arthralgia 16 1.2
Myalgia 13 0
Respiratory, thoracic and mediastinal disorders
Cough 16 0
Dyspnea 14 0
Psychiatric disorders
Anxiety 10 0

Other adverse reactions (<10%) include epistaxis (7%), weight decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%), and stomatitis (1%).

Table 6: Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
1. Number of patients with both baseline and post-baseline results for each test
2. NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for all other laboratory parameters.
3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
Laboratory AbnormalityTUKYSA + Trastuzumab
N=851
All Grades%Grade 3%Grade 4%
Hematology
Decreased hemoglobin 46 3.5 0
Decreased lymphocytes 39 12 0
Decreased leukocytes 22 0 0
Decreased platelets 15 0 0
Chemistry
Increased creatinine2,3 58 0 0
Increased glucose 56 2.4 0
Increased ALT 46 2.4 2.4
Increased AST 33 2.4 3.5
Increased bilirubin 28 3.5 2.4
Increased alkaline phosphatase 25 1.2 0
Decreased albumin 24 1.2 0
Decreased sodium 20 6 0
Decreased potassium 16 1.2 0

Increased Creatinine

The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible in 87% of patients with values outside normal lab limits upon treatment completion.  Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].
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