(tucatinib)

Prescribing Information
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12 CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

     

12.1 Mechanism of Action

Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.

12.2 Pharmacodynamics

Exposure-Response Relationship

Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

Cardiac Electrophysiology

No large mean increase in QTc (i.e., >20 ms) was detected following treatment with TUKYSA at the recommended dose of 300 mg taken orally twice daily.

12.3 Pharmacokinetics

Tucatinib AUC0-INF and Cmax increased proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Time to steady state was approximately 4 days. Steady-state pharmacokinetic parameters following administration of TUKYSA 300 mg twice daily for 7 days in patients with mBC and mCRC are described in Table 12. The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold.

Table 12: Tucatinib Cmax and AUC

Tumor Type

AUCss (ng*h/mL)

Cmax,ss (ng/mL)

Ctrough,ss (ng/mL)

mBC

5620 (43)

747 (45)

288 (59)

mCRC

3370 (49)

405 (45)

197 (63)

Absorption

The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).

Effects of Food

Following administration of a single oral dose of TUKYSA in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC0-INF increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4 hours, and Cmax was unaltered. The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful.

Distribution

The geometric mean (CV%) apparent volume of distribution of tucatinib at steady-state were 903 (42) L and 829 (21) L in patients with mBC and mCRC, respectively. The plasma protein binding was 97.1% at clinically relevant concentrations.

At steady-state, concentrations of tucatinib and its metabolite ONT-993 in the cerebrospinal fluid were comparable to unbound plasma concentrations.

Elimination

At steady-state, tucatinib effective half-life was approximately 11.9 hours and geometric mean (CV%) apparent clearance was 53 (43) L/h in patients with mBC. Tucatinib effective half-life was approximately 16.4 hours and geometric mean (CV%) apparent clearance was 89 (49) L/h in patients with mCRC.

Metabolism

Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.

Excretion

Following a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 90% within 13 days post-dose. In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.

Specific Populations

Age (18-77 years), albumin (19 to 52 g/L), creatinine clearance (CLcr: 60 to 89 mL/min (n = 63); CLcr 30 to 59 mL/min (n = 6)), body weight (41 to 146 kg), sex (male (n = 170), female (n = 113)) and race (White (n = 205), Black (n = 37), or Asian (n = 25)) did not have a clinically meaningful effect on tucatinib exposure.

Renal Impairment

No clinically significant differences in the pharmacokinetics of tucatinib were observed in patients with mild to moderate renal impairment (CLcr: 30 to 89 mL/min by Cockcroft-Gault). The effect of severe renal impairment (CLcr: <30 mL/min) on the pharmacokinetics of tucatinib is unknown.

Hepatic Impairment

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure. Tucatinib AUC0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies

Table 13: Effect of Other Drugs on TUKYSA

Concomitant Drug
(Dose)

TUKYSA Dose

Ratio (90% CI) of Tucatinib
Exposure With and Without
Concomitant Drug

Cmax

AUC

Strong CYP3A Inhibitor
Itraconazole (200 mg BID)

300 mg single dose

1.3
(1.2, 1.4)

1.3
(1.3, 1.4)

Strong CYP3A/Moderate 2C8 Inducer
Rifampin (600 mg once daily)

0.6
(0.5, 0.8)

0.5
(0.4, 0.6)

Strong CYP2C8 Inhibitor
Gemfibrozil (600 mg BID)

1.6
(1.5, 1.8)

3.0
(2.7, 3.5)

Table 14: Effect of TUKYSA on Other Drugs
*
Tucatinib reduced the renal clearance of metformin without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C.

Concomitant Drug
(Dose)

TUKYSA Dose

Ratio (90% CI) of Exposure
Measures of Concomitant Drug
with/without Tucatinib

Cmax

AUC

CYP2C8 Substrate
Repaglinide (0.5 mg single dose)

300 mg twice daily

1.7
(1.4, 2.1)

1.7
(1.5, 1.9)

CYP3A Substrate
Midazolam (2 mg single dose)

3.0
(2.6, 3.4)

5.7
(5.0, 6.5)

P-gp Substrate
Digoxin (0.5 mg single dose)

2.4
(1.9, 2.9)

1.5
(1.3, 1.7)

MATE1/2-K substrate*
Metformin (850 mg single dose)

1.1
(1.0, 1.2)

1.4
(1.2, 1.5)

No clinically significant difference in the pharmacokinetics of tucatinib were observed when used concomitantly with omeprazole (proton pump inhibitor) or tolbutamide (sensitive CYP2C9 substrate).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Tucatinib is a reversible inhibitor of CYP2C8 and CYP3A and a time-dependent inhibitor of CYP3A, but is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Tucatinib is not an inhibitor of UGT1A1.

Transporter Systems: Tucatinib is a substrate of P-gp and BCRP, but is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, or BSEP.

Tucatinib inhibits MATE1/MATE2-K-mediated transport of metformin and OCT2/MATE1-mediated transport of creatinine. The observed serum creatinine increase in clinical studies with tucatinib is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1.

Medication Guide

MEDICATION GUIDE

   

This Medication Guide has been approved by the U.S. Food and Drug Administration.  Revised: 10/2026

MEDICATION GUIDE

TUKYSA® (too-KYE-sah)

(tucatinib)

tablets

Important: If your healthcare provider prescribes TUKYSA in combination with capecitabine or pertuzumab, also read the Patient Information that comes with capecitabine or pertuzumab.

What is the most important information I should know about TUKYSA?

TUKYSA can cause serious side effects, including:

•
Liver Problems. TUKYSA can cause severe liver problems that can lead to death, especially if you restart TUKYSA after previously stopping treatment due to liver problems. Your healthcare provider will do blood tests to check your liver function before starting treatment with TUKYSA, every 2 weeks for the first 2 months, and then every 3 weeks during treatment with TUKYSA, or as needed. Tell your healthcare provider right away if you get 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
feeling very tired
o
decreased appetite
o
bleeding or bruising more easily than normal
•
Diarrhea. TUKYSA can cause severe diarrhea that can lead to loss of too much body fluids (dehydration), low blood pressure, kidney problems, and death. Tell your healthcare provider right away if you have a change in your bowel movements or severe diarrhea. Your healthcare provider may prescribe medicines to treat your diarrhea during treatment with TUKYSA.

See “What are the possible side effects of TUKYSA?” for more information about side effects.

What is TUKYSA?

TUKYSA is a prescription medicine used in adults:

•
in combination with the medicines trastuzumab and pertuzumab for maintenance treatment of a type of breast cancer called human epidermal growth factor receptor-2 (HER2)-positive breast cancer that has spread:
o
to nearby tissue or lymph nodes and cannot be removed by surgery (unresectable locally advanced) or
o
to other parts of the body (metastatic).
•
in combination with trastuzumab and capecitabine to treat HER2-positive breast cancer that has spread to other parts of the body (metastatic), or cannot be removed by surgery, who have received 1 or more anti-HER2 metastatic breast cancer treatments.
•
in combination with the medicine trastuzumab to treat a type of colorectal cancer called RAS wild-type HER2-positive colorectal cancer that has spread to other parts of the body (metastatic), or cannot be removed by surgery, who have received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and it did not work or is no longer working.

Your healthcare provider will perform a test to make sure TUKYSA is right for you.

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
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
Your healthcare provider will tell you how long you should use birth control (contraception) after your treatment with trastuzumab, pertuzumab, or capecitabine.
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:
o
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. Your healthcare provider will tell you how long you should not breastfeed after your treatment with trastuzumab and pertuzumab.

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.
•
Follow your healthcare provider’s instruction for taking TUKYSA with the medicines trastuzumab, trastuzumab and capecitabine, or trastuzumab and pertuzumab.
•
Take TUKYSA 2 times a day, with or without a meal.
•
Take TUKYSA about 12 hours apart and 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 can cause serious side effects, including:

•
See “What is the most important information I should know about TUKYSA?”

The most common side effects of TUKYSA in combination with trastuzumab and pertuzumab in adults with HER2-positive breast cancer include:

•
diarrhea
•
muscle and joint pain
•
liver problems
•
nausea
•
tiredness
•
rash
•
vomiting

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
•
liver problems
•
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 between 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 the reach of children.

General information about the safe and effective use of TUKYSA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. 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 health 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.

This product’s labeling may have been updated. For the most recent prescribing information, please visit https://www.pfizer.com.

Manufactured for: Seagen Inc., Bothell, WA 98021
TUKYSA is a registered trademark owned by Seagen Inc.
©2026 Seagen Inc.
For more information, call 1-800-438-1985.
LAB-1594-1.0

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