Dosing & Uses
Dosage Forms & Strengths
tablet
- 50mg
- 150mg
Advanced or Metastatic Breast Cancer
Indicated in combination with trastuzumab and capecitabine for treatment of advanced unresectable or metastatic human epidermal growth factor (HER2)-positive breast cancer (including brain metastases) in patients who have received ≥1 anti-HER2-based regimens in the metastatic setting
300 mg PO BID in combination with trastuzumab and capecitabine
Continue until disease progression or unacceptable toxicity
Refer to the full prescribing information for trastuzumab and capecitabine for additional information
Colorectal Cancer
Indicated in combination with trastuzumab for RAS wild-type HER 2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
300 mg PO BID
Continue until disease progression or unacceptable toxicity
Refer to the full prescribing information for trastuzumab for additional inforation
Dosage Modifications
Refer to the full prescribing information for trastuzumab and capecitabine for dosage modifications
Dose reductions for adverse reactions
- First reduction: 250 mg PO BID
- Second reduction: 200 mg PO BID
- Third reduction: 150 PO BID
- Unable to tolerate 150 mg PO BID: Permanently discontinue
Diarrhea
- Grade 3 without antidiarrheal treatment: Initiate or intensify appropriate medical therapy; hold until recovery to Grade ≤1, then resume at same dose
- Grade 3 with antidiarrheal therapy: Initiate or intensify appropriate medical therapy; hold until recovery to Grade ≤1, then resume at same dose or at next lower dose
- Grade 4: Permanently discontinue
Hepatotoxicity
- Grade 2 bilirubin (>1.5 to 3x ULN): Hold until recovery to Grade ≤1, then resume at same dose
- Grade 3 ALT or AST (>5 to 20x ULN) OR Grade 3 bilirubin (>3 to 10x ULN): Hold until recovery to Grade ≤1, then resume at next lower dose
-
Permanently discontinue
- Grade 4 ALT/AST (>20x ULN) OR Grade 4 bilirubin (>10x ULN)
- ALT/AST >3x ULN AND bilirubin >2x ULN
Other adverse reactions
- Grade 3: Hold until recovery to Grade ≤1, then resume at next lower dose level
- Grade 4: Permanently discontinue
Coadministration with strong CYP2C8 inhibitors
- Avoid coadministration; if unavoidable, reduce tucatinib to 100 mg PO BID
- After discontinuing strong CYP2C8 inhibitor for 3 elimination half-lives, resume tucatinib dose taken before initiating inhibitor
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
- Severe (CrCl <30 mL/min): Use in combination with trastuzumab and capecitabine is not recommended; capecitabine is contraindicated in patients with severe renal impairment
Hepatic impairment
- Mild-to-moderate (Child-Pugh A or B): No dosage adjustment necessary
- Severe (Child-Pugh C): Reduce to 200 mg BID
Dosing Considerations
Verify pregnancy status of females of reproductive potential before initiating
Select patients for unresectable or metastatic colorectal cancer
- Based on presence of HER2 overexpression or gene amplification and RAS wild-type
- Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics
Safety and efficacy not established
Adverse Effects
>10%
All grades (BC)
- Diarrhea (81%)
- Palmoplantar erythrodysesthesia syndrome (63%)
- Decreased hemoglobin (59%)
- Nausea (58%)
- Decreased phosphate (57%)
- Increased bilirubin (47%)
- Increased ALT (46%)
- Increased AST (43%)
- Hepatotoxicity (42%)
- Decreased magnesium (40%)
- Vomiting (36%)
- Decreased potassium (36%)
- Increased creatinine (33%)
- Stomatitis (32%)
- Decreased sodium (28%)
- Increased alkaline phosphatase (26%)
- Decreased appetite (25%)
- Anemia (21%)
- Rash (20%)
- Arthralgia (15%)
- Increased creatinine (14%)
- Decreased weight (13%)
- Peripheral neuropathy (13%)
- Epistaxis (12%)
All grades (mCRC)
- Diarrhea (64%)
- Increased creatinine (58%)
- Increased glucose (56%)
- Decreased hemoglobin (46%)
- Increased ALT (46%)
- Fatigue (44%)
- Decreased lymphocytes (39%)
- Rash (37%)
- Nausea (35%)
- Increased AST (33%)
- Increased bilirubin (28%)
- Increased alkaline phosphatase (25%)
- Decreased albumin 24%)
- Decreased leukocytes (22%)
- Abdominal pain (21%)
- Infusion-related reaction (21%)
- Pyrexia (20%)
- Decreased sodium (20%)
- Chills (19%)
- Decreased appetite (19%)
- Back pain (17%)
- Vomiting (16%)
- Arthralgia (16%)
- Cough (16%)
- Decreased potassium (16%)
- Decreased platelets (15%)
- Constipation (14%)
- Dyspnea (14%)
- Myalgia (13%)
Grade 3 to 4 (BC)
- Palmoplantar erythrodysesthesia syndrome (13%)
- Diarrhea (0.5-12%)
Grade 3 or 4 (mCRC)
- Decreased lymphocytes (12%)
1-10%
Grade 3 to 4 (BC)
- Hepatoxicity (0.2-9%)
- Increased ALT (8%)
- Decreased phosphate (8%)
- Increased AST (6%)
- Decreased potassium (6%)
- Anemia (3.7%)
- Nausea (3.7%)
- Decreased hemoglobin (3.3%)
- Vomiting (3%)
- Stomatitis (2.5%)
- Decreased sodium (2.5%)
- Increased bilirubin (1.5%)
- Decreased weight (1%)
Grade 3 or 4 (mCRC)
- Anemia (10%)
- Anxiety (10%)
- Hypertension (7%)
- Decreased sodium (6%)
- Diarrhea (3.5%)
- Decreased hemoglobin (3.5%)
- Increased AST (2.4-3.5%)
- Increased bilirubin (2.4-3.5%)
- Increased glucose (2.4%)
- Increased ALT (2.4%)
- Abdominal pain (2.3%)
- Fatigue (2.3%)
- Back pain (2.3%)
- Constipation (1.2%)
- Chills (1.2%)
- Arthralgia (1.2%)
- Increased alkaline phosphatase (1.2%)
- Decreased bilirubin (1.2%)
- Decreased potassium (1.2%)
<1%
Grade 3 to 4 (BC)
- Decreased magnesium (0.8%)
- Rash (0.7%)
- Arthralgia (0.5%)
- Peripheral neuropathy (0.5%)
- Increased alkaline phosphatase (0.5%)
- Decreased appetite (0.5%)
Warnings
Contraindications
None
Cautions
Severe hepatotoxicity has been report; monitor ALT, AST, and bilirubin prior to initiation, q3Weeks during treatment, and as clinically indicated
May cause fetal harm
Diarrhea
- Severe diarrhea, including dehydration, acute kidney injury, and death, has been reported
- Administer antidiarrheal treatment as clinically indicated
- Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea
Drug interaction overview
Tucatinib is a substrate of CYP3A4, CYP2C8, P-glycoprotein (P-gp), and BCRP
Also, reversible inhibitor of CYP3A4 and CYP2C8; time-dependent inhibitor of CYP3A4; P-gp inhibitor
-
Strong CYP3A or moderate CYP2C8 inducers
- Avoid coadministration
- Concomitant use of tucatinib with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations, which may reduce the efficacy of tucatinib
-
CYP2C8 inhibitors
- Avoid coadministration with strong CYP2C8 inhibitors; reduce tucatinib dose if concomitant use cannot be avoided
- Concomitant use of tucatinib with a strong CYP2C8 inhibitor may increase tucatinib plasma concentrations, which may increase the risk of tucatinib toxicity
- Coadministration with moderate CYP2C8 inhibitors: Increase monitoring for tucatinib toxicity
-
CYP3A substrates
- Avoid coadministration with sensitive CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities
-
P-gp substrates
- Consider reducing dose of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities
Pregnancy & Lactation
Refer to the full prescribing information of trastuzumab and capecitabine for pregnancy and lactation information
Pregnancy
Based on animal data and its mechanism of action, fetal harm may occur when administer to pregnant females
No data available on use in pregnant females to inform a drug-associated risk
Verify pregnancy status of females of reproductive potential before treatment
Contraception
- Females of reproductive potential or males with female partners of reproductive potential: Use effective contraception during treatment and at least 1 week after final dose
Infertility
- May impair male and female fertility
Animal data
- Administration to pregnant rats and rabbits during organogenesis resulted in embryofetal mortality, reduced fetal weight, and fetal abnormalities at maternal exposure ≥1.3x the AUC at the recommended dose
- Advise pregnant women and females of reproductive potential of potential risk to fetus
Lactation
No data available on the presence of tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production
Advise females not to breastfeed during treatment and for at least 1 week after final dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Tyrosine kinase inhibitor for HER2
Inhibits HER2 and HER3 phosphorylation in vitro, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed antitumor activity in HER2 expressing tumor cells
In vivo, tucatinib inhibited growth of HER2 expressing tumors
Absorption
Peak plasma time: ~2 hr
Steady-state reached at ~4 days
Distribution
Vd: 1670 L
Protein bound: 97.1%
Metabolism
Metabolized primarily by CYP2C8 and to a lesser extent via CYP3A
Elimination
Half-life: ~8.5 hr
Clearance: 148 L/hr
Excretion
- Feces: ~86% (16% unchanged)
- Urine: 4.1%
- Plasma: ~76% unchanged (19% metabolites)
Administration
Oral Administration
Take with or without meals
Note: Capecitabine is given PO BID and taken within 30 min after a meal
When given in combination, tucatinib and capecitabine can be taken at the same time
Swallow tablets whole; do not chew, crush, or split before swallowing
Do not ingest tablet if broken, cracked, or not otherwise intact
Take ~12 hr apart and at the same time each day
Missed or vomited dose: Take next dose at usual scheduled time
Storage
Store at room temperature, 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
Dispense and store in original container only to protect from moisture
Replace cap securely each time after opening
Do not discard desiccant
Once opened, use within 3 months; discard any unused tablets 3 months after opening
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Formulary
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