I. Drug Name

Generic Name: Tucatinib

English Name: Tucatinib

Brand Names: Tukysa, Tukadx

Dosage Form: Oral Film-Coated Tablets

Specification: 150 mg per tablet; 60 tablets per box

Manufacturer: Laos Daxiong Pharmaceutical Co., Ltd.

Regulatory Approval Number: 08 L1002123

II. Pharmacological Actions

Pharmacological Classification: Tyrosine Kinase Inhibitor (TKI)

Mechanism of Action: Tucatinib is a highly selective, orally bioavailable HER2 tyrosine kinase inhibitor.

HER2 (Human Epidermal Growth Factor Receptor 2) is a protein that is overexpressed on the surface of certain cancer cells (such as those in breast cancer and gastric cancer), where it promotes cancer cell growth and division.

By highly selectively inhibiting HER2, Tucatinib blocks its downstream signaling pathways, thereby inhibiting cancer cell growth and inducing apoptosis.

Compared to other drugs in its class, Tucatinib demonstrates significantly higher selectivity for HER2 than for EGFR (Epidermal Growth Factor Receptor); this is considered to be one of the reasons for its lower incidence of side effects, such as diarrhea.

III. Indications

Tucatinib is indicated in combination with Trastuzumab and Capecitabine for the treatment of adult patients with HER2-positive breast cancer who meet the following criteria:

Unresectable locally advanced or metastatic disease.

Have previously received at least one anti-HER2-based regimen in the metastatic setting.

IV. Dosage and Administration

Recommended Dosage:

Tucatinib: 300 mg (two 150 mg tablets), taken orally twice daily (approximately every 12 hours).

Trastuzumab: Administered via intravenous infusion at the standard dosage.

Capecitabine: 1000 mg/m², taken orally twice daily (once in the morning and once in the evening) on Days 1 through 14 of a 21-day cycle.

Method of Administration:

Swallow the tablets whole; do not chew, crush, or split the tablets. May be taken with or without food.

If vomiting occurs or a dose is missed after taking the medication, the missed dose should not be taken; instead, wait until the next scheduled time to take the regular dose.

V. Contraindications

Patients with a history of severe hypersensitivity to tucatinib or to any of the excipients.

VI. Warnings and Precautions

1. Severe Diarrhea:

Diarrhea is a common adverse reaction that may be severe and lead to dehydration, hypotension, and renal impairment.

At the onset of treatment, patients should be provided with anti-diarrheal medication (e.g., loperamide) to have on hand and should use it immediately upon the first occurrence of loose stools.

If severe diarrhea occurs, tucatinib should be interrupted based on clinical indication until improvement to Grade ≤1, and then resumed at the same or a reduced dose. Hydration and electrolytes should be replenished concurrently.

2. Hepatotoxicity:

Tucatinib may cause severe hepatotoxicity.

ALT (alanine aminotransferase), AST (aspartate aminotransferase), and bilirubin levels must be monitored prior to initiating treatment, and every 3 weeks during treatment.

Depending on the severity of the hepatotoxicity, dose interruption, dose reduction, or permanent discontinuation of the drug may be required.

3. Embryo-Fetal Toxicity:

Based on its mechanism of action, tucatinib may cause fetal harm when administered to a pregnant woman.

Females of reproductive potential should use effective contraception during treatment and for at least 1 week after the last dose.

Male patients with female partners who are pregnant or of reproductive potential should use condoms during treatment and for at least 1 week after the last dose.

VII. Adverse Reactions

Very Common (>10%) Severe and/or Major Adverse Reactions:

Gastrointestinal: Diarrhea (may be severe), nausea, vomiting, abdominal pain, stomatitis.

Hepatobiliary: Hepatotoxicity (elevated ALT/AST, hyperbilirubinemia).

Skin and Subcutaneous Tissue: Rash, pruritus.

General Disorders: Fatigue, pyrexia.

Blood and Lymphatic System: Anemia.

Metabolism and Nutrition: Decreased appetite.

Nervous System: Headache. Laboratory Abnormalities:

Elevated creatinine, decreased phosphate, decreased hemoglobin, lymphopenia.

VIII. Drug Interactions

Strong CYP3A Inhibitors (e.g., clarithromycin, itraconazole, ritonavir):

Co-administration significantly increases plasma concentrations of tucatinib, thereby increasing the risk of adverse reactions.

Co-administration should be avoided. If co-administration is unavoidable, the tucatinib dosage should be reduced to 100 mg, twice daily.

Strong CYP2C8 Inhibitors (e.g., gemfibrozil):

Co-administration increases plasma concentrations of tucatinib.

If co-administration is unavoidable, adverse reactions should be closely monitored, and a reduction in the tucatinib dosage should be considered.

Strong CYP3A Inducers (e.g., rifampin, carbamazepine, St. John's wort):

Co-administration significantly decreases plasma concentrations of tucatinib, potentially compromising efficacy.

Co-administration should be avoided.

P-gp Substrates (e.g., digoxin, dabigatran etexilate):

Tucatinib may inhibit the P-gp transporter, thereby increasing the plasma concentrations of these co-administered drugs.

When co-administering, adverse reactions associated with these substrate drugs should be closely monitored, and a reduction in their dosages should be considered.

IX. Use in Specific Populations

Pregnant Women: May cause fetal harm. Advise pregnant women of the potential risk to the fetus.

Lactating Women: It is not known whether tucatinib is excreted in human milk. Given the potential for serious adverse reactions in breastfed infants, it is recommended to discontinue breastfeeding during treatment and for at least 1 week following the last dose.

Pediatric Patients: Safety and efficacy have not been established.

Geriatric Patients: No overall differences in safety were observed between patients aged 65 and older and younger patients; however, caution should still be exercised.

Patients with Hepatic/Renal Impairment:

Hepatic Impairment:

For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, the recommended dosage should be reduced to 200 mg, twice daily.

For patients with severe (Child-Pugh C) hepatic impairment, the recommended dosage should be reduced to 150 mg, twice daily. Renal Impairment:

For patients with mild to moderate renal impairment (eGFR 30–89 mL/min/1.73 m²), no dose adjustment is required.

For patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or those requiring dialysis, clinical data are limited; therefore, caution is advised.

X. Overdosage

Symptoms: Expected symptoms include an exacerbation of adverse reactions, such as severe diarrhea, nausea, vomiting, and hepatotoxicity.

Management: There is no specific antidote. General supportive measures should be instituted, including close monitoring of vital signs and adverse reactions, as well as symptomatic treatment.

XI. Clinical Pharmacology

Pharmacokinetics: Tucatinib is well absorbed following oral administration, reaching peak plasma concentrations approximately 2 hours after dosing. High-fat meals increase its systemic exposure. *In vivo*, it is primarily metabolized via CYP2C8 and CYP3A4. Fecal excretion is the primary route of elimination.

XII. Patient Counseling Information

1. Adherence to Prescribing Instructions: Take the medication strictly according to the dose and schedule prescribed by your physician; do not alter the regimen on your own.

2. Diarrhea Management: Understand how to prevent and manage diarrhea; keep anti-diarrheal medications on hand, and promptly report any severe or persistent diarrhea to your physician.

3. Liver Function Monitoring: Understand the importance of periodic blood tests to monitor liver function.

4. Contraception Requirements: Female and male patients of reproductive potential must understand and adhere to the required contraceptive measures.

5. Reporting Signs of Infection: Report any signs of infection, such as fever, chills, or a persistent cough.

6. Disclosure of Medication History: Before seeking medical care or starting any new medications, inform your physician that you are taking Tucatinib to avoid potential drug interactions.

7. Storage: Store at room temperature in the original packaging, protected from moisture.

In closing, we emphasize once again: Please strictly follow the specific instructions provided by your treating physician and pharmacist. If you have any questions or experience any discomfort during the course of treatment, please communicate immediately with your healthcare team.