TUKYSA® (tucatinib) 6 ADVERSE REACTIONS

(tucatinib)

Prescribing Information

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)
* 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 † 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 ‡ 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 § Anemia includes anemia, hemoglobin decreased, and normocytic anemia ¶ Due to inhibition of renal tubular transport of creatinine without affecting glomerular function # Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy
Adverse Reaction	TUKYSA + Trastuzumab + Capecitabine N = 404			Placebo + Trastuzumab + Capecitabine N = 197
Adverse Reaction	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
Stomatitis*	32	2.5	0	21	0.5	0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	63	13	0	53	9	0
Rash†	20	0.7	0	15	0.5	0
Hepatobiliary disorders
Hepatotoxicity‡	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
Anemia§	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 increased¶	14	0	0	1.5	0	0
Weight decreased	13	1	0	6	0.5	0
Nervous System Disorders
Peripheral neuropathy#	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
* 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). † Laboratory criteria for Grade 1 is identical to laboratory criteria for Grade 2. ‡ Due to inhibition of renal tubular transport of creatinine without affecting glomerular function. § There is no definition for Grade 2 in CTCAE v.4.03.
Laboratory Abnormality	TUKYSA + Trastuzumab +Capecitabine*		Placebo + Trastuzumab +Capecitabine*
Laboratory Abnormality	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†	36	6	31	5
Increased creatinine‡	33	0	6	0
Decreased sodium§	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. † Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper. ‡ 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*
Adverse Reaction	All Grades %	Grade 3 %
Gastrointestinal disorders
Diarrhea	64	3.5
Nausea	35	0
Vomiting	16	0
Abdominal pain†	21	2.3
Constipation	14	1.2
General disorders
Fatigue	44	2.3
Pyrexia	20	0
Chills	19	1.2
Skin and subcutaneous disorders
Rash‡	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)
* Number of patients with both baseline and post-baseline results for each test † NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for all other laboratory parameters. ‡ Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
Laboratory Abnormality	TUKYSA + Trastuzumab N=85*
Laboratory Abnormality	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 creatinine†,‡	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)].

Medication Guide

MEDICATION GUIDE

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 01/2023
PATIENT INFORMATION TUKYSA® (too-KYE-sah) (tucatinib) tablets
Important information: If your healthcare provider prescribes TUKYSA in combination with capecitabine for your breast cancer, also read the Patient Information that comes with capecitabine.
What is TUKYSA? TUKYSA is a prescription medicine used to treat adults with: • a type of breast cancer called human epidermal growth factor receptor-2 (HER2)-positive breast cancer. TUKYSA is used with the medicines trastuzumab and capecitabine, when your cancer has spread to other parts of the body such as the brain (metastatic), or cannot be removed by surgery, and you have received one or more anti-HER2 breast cancer treatments. • a type of colorectal cancer called RAS wild-type HER2-positive colorectal cancer. TUKYSA is used with the medicine trastuzumab, when your cancer has spread to other parts of the body (metastatic), or cannot be removed by surgery, and you have received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and it did not work or is no longer working. It is not known if TUKYSA is safe and effective in children.
Before taking TUKYSA, tell your healthcare provider about all of your medical conditions, including if you:
• have liver problems. • are pregnant or plan to become pregnant. TUKYSA can harm your unborn baby. Females who are able to become pregnant: o Your healthcare provider will do a pregnancy test before you start treatment with TUKYSA. o You should use effective birth control (contraception) during treatment with TUKYSA and for 1 week after the last dose of TUKYSA. Talk with your healthcare provider about forms of birth control that you can use during this time. o Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TUKYSA. Males with female partner who are able to become pregnant should use effective birth control during treatment with TUKYSA and for 1 week after the last dose of TUKYSA. • are breastfeeding or plan to breastfeed. It is not known if TUKYSA passes into your breast milk. Do not breastfeed during treatment with TUKYSA and for 1 week after the last dose of TUKYSA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TUKYSA may affect the way your other medicines work, and other medicines may affect the way TUKYSA works. Know the medicines you take. Keep a list of all the medicines you take and show it to your healthcare provider and pharmacist every time you get a new medicine.
How should I take TUKYSA?
• Take TUKYSA exactly as your healthcare provider tells you. • TUKYSA is used with the medicine trastuzumab for colorectal cancer or with trastuzumab and capecitabine for breast cancer. Your healthcare provider will tell you the dose of trastuzumab and capecitabine you will take and how you will receive them. • Take TUKYSA 2 times a day, with or without a meal. • Take TUKYSA about 12 hours apart or at the same times every day. • Swallow TUKYSA tablets whole. Do not chew, crush, or split TUKYSA tablets before swallowing. Do not take TUKYSA tablets if they are broken, cracked, or damaged. • If you vomit or miss a dose of TUKYSA, take your next dose at your regular time.
What are the possible side effects of TUKYSA? TUKYSA may cause serious side effects, including:
• Diarrhea. Diarrhea is common with TUKYSA and can sometimes be severe. Tell your healthcare provider if you have a change in your bowel movements or severe diarrhea. Severe diarrhea can lead to loss of too much body fluids (dehydration), low blood pressure, kidney problems and death. Your healthcare provider may prescribe medicines to treat your diarrhea during treatment with TUKYSA. • Liver Problems. TUKYSA can cause severe liver problems. Your healthcare provider will do blood tests to check your liver function before and every 3 weeks during treatment with TUKYSA, or as needed. Tell your healthcare provider right away if you have any signs and symptoms of liver problems including:
	o itching o yellowing of your skin or eyes o dark or brown urine (tea-colored) o pain in the upper right side of your stomach-area (abdomen)		o feel very tired o decreased appetite o bleeding or bruising more easily than normal
The most common side effects of TUKYSA in combination with trastuzumab and capecitabine in adults with HER2-positive breast cancer include:
• diarrhea • rash, redness, pain, swelling or blisters on the palms of your hands or soles of your feet • nausea • increased liver function blood tests • vomiting		• mouth sores (stomatitis) • decreased appetite • low red blood cell counts (anemia) • rash
The most common side effects of TUKYSA in combination with trastuzumab in adults with RAS wild-type HER2-positive colorectal cancer include:
• diarrhea • tiredness • rash		• nausea • stomach-area (abdomen) pain • infusion-related reactions • fever
Your healthcare provider may change your dose of TUKYSA, temporarily stop, or permanently stop treatment with TUKYSA if you have certain side effects. TUKYSA may cause fertility problems in males and females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility. These are not all of the possible side effects of TUKYSA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TUKYSA?
• Store TUKYSA at room temperature 68°F to 77°F (20ºC to 25ºC). • Keep TUKYSA in its original container. The TUKYSA bottle contains a desiccant packet to help keep your tablets dry (protect from moisture). Keep the desiccant in the bottle. • Tightly close the bottle of TUKYSA after you take your dose. • TUKYSA must be used within 3 months after opening the bottle. Throw away (discard) any unused tablets 3 months after opening the bottle.
Keep TUKYSA and all medicines out of reach of children.
General information about the safe and effective use of TUKYSA. Medicines are sometimes prescribed for conditions not listed in the Patient Information. Do not use TUKYSA for a condition for which it was not prescribed. Do not give TUKYSA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TUKYSA that is written for healthcare professionals.
What are the ingredients in TUKYSA? Active ingredient: tucatinib Inactive ingredients: Tablet core: copovidone, crospovidone, sodium chloride, potassium chloride, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. Tablet coating: yellow film coat: polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, and yellow iron oxide non-irradiated. Manufactured for: Seagen Inc., Bothell, WA 98021 TUKYSA is a registered trademark owned by Seagen Inc. ©2023 Seagen Inc. PPI-213411-v04 For more information, call 1-855-473-2436 (1-855-4SEAGEN) or go to www.TUKYSA.com.

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