tucatinib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications: Genetic Implications

Pronunciation:
too-ka-ti-nib


Trade Name(s)

  • Tukysa

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

  • Genetic implication  Advanced unresectable or metastatic HER2-positive breast cancer in patients who previously received ≥1 anti-HER2-based regimens in the metastatic setting (in combination with trastuzumab and capecitabine).
  • Genetic implication  RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (in combination with trastuzumab).

Action

Genetic implication Acts as tyrosine kinase inhibitor of HER2, thereby inhibiting the growth of HER2-expressing tumors.

Therapeutic Effect(s):

  • Improved survival and progression-free survival in metastatic breast cancer.
  • Decreased spread of colorectal cancer.

Pharmacokinetics

Absorption: High-fat foods increase extent of and delay absorption.

Distribution: Extensively distributed to extravascular tissues.

Metabolism and Excretion: Primarily metabolized by the liver via the CYP2C8 isoenzyme and to a lesser extent by the CYP3A4 isoenzyme. Primarily excreted in feces (86%; 16% as unchanged drug), with 4% being excreted in urine.

Half-life: 8.5 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown1–4 hr12 hr

Contraindication/Precautions

Contraindicated in:

  • Severe renal impairment;
  • OB:   Pregnancy;
  • Lactation:  Lactation.

Use Cautiously in:

  • Severe hepatic impairment (↓ dose);
  • Rep:   Women of reproductive potential and men with female partners of reproductive potential;
  • Pedi:   Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

Derm: palmar-plantar erythrodysesthesia, rash

EENT: epistaxis

F and E: hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia

GI: abdominal pain, DIARRHEA, HEPATOTOXICITY, hyperbilirubinemia, ↑ liver enzymes, nausea, stomatitis, vomiting

GU: ↑ serum creatinine, ↓ fertility

Hemat: anemia

Metabolic: ↓ appetite, weight loss

MS: arthralgia

Neuro: fatigue, headache, peripheral neuropathy

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Strong CYP2C8 inhibitors, including  gemfibrozil, may ↑ levels and risk of toxicity; avoid concurrent use.
  •  Strong CYP3A4 inducers  or  moderate CYP2C8 inducers, including  rifampin, may ↓ levels and effectiveness; avoid concurrent use.
  • May ↑ levels and risk of toxicity of  CYP3A4 substrates ; avoid concurrent with CYP3A4 substrates with narrow therapeutic range; if concurrent use unavoidable, ↓ dose of CYP3A4 substrate.
  • May ↑ levels and risk of toxicity of  P-glycoprotein substrates ; consider ↓ dose of P-glycoprotein substrates with narrow therapeutic ranges.

Route/Dosage

PO (Adults): 300 mg twice daily; continue until disease progression or unacceptable toxicity.  Concurrent use of strong CYP2C8 inhibitors: 100 mg twice daily; continue until disease progression or unacceptable toxicity.

Hepatic Impairment 
PO (Adults): Severe hepatic impairment: 200 mg twice daily; continue until disease progression or unacceptable toxicity.

Availability

Tablets: 50 mg, 150 mg

Assessment

  • Monitor for diarrhea. Usually occurs within 12 days and takes 8 days to resolve. Administer antidiarrheals and perform diagnostic tests to exclude other causes.  If Grade 3 diarrhea occurs without antidiarrheal treatment:  Begin or intensify medical therapy. Hold tucatinib until recovery to ≤ Grade 1; then resume at the same dose level.  If Grade 3 diarrhea occurs with antidiarrheal treatment: Begin or intensify medical therapy. Hold tucatinib until recovery to ≤ Grade 1; then resume at next lower dose level.  If Grade 4 diarrhea occurs:  Permanently discontinue tucatinib.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

Genetic implication Determine RAS mutation status using FDA-approved tests prior to initiating treatment. Only patients whose colorectal tumors are RAS wild-type should receive tucatinib.

  • Monitor ALT, AST, and bilirubin before starting tucatinib, every 3 wk during therapy, and as clinically indicated.  If Grade 2 bilirubin (>1.5 to 3 times upper limit of normal [ULN]) occurs:  Hold tucatinib until recovery to ≤ Grade 1; then resume at the same dose level.  If Grade 3 ALT or AST (> 5–20 times ULN) OR Grade 3 bilirubin (> 3–10 times ULN) occurs: Hold tucatinib until recovery to ≤ Grade 1; then resume at the next lower dose level.  If Grade 4 ALT or AST (> 20 times ULN) OR Grade 4 bilirubin (> 10 times ULN) occurs: Permanently discontinue tucatinib.  If ALT or AST > 3 times ULN AND bilirubin > 2 times ULN: Permanently discontinue tucatinib.
  • May cause decreased hemoglobin, phosphate, magnesium, potassium, and sodium and increased serum creatinine.

Implementation

  • Dose Reduction Schedule: 1st reduction:  250 mg twice daily.  2nd reduction:  200 mg twice daily.  3rd reduction: 150 mg twice daily.  If unable to tolerate 150 mg twice daily,  permanently discontinue tucatinib.
  • PO Administer twice daily about 12 hr apart without regard to food.  DNC: Swallow tablet whole; do not chew, crush, or split. Do not administer tablets that are broken, cracked, or not intact. 

Patient/Family Teaching

  • Instruct patient to take as directed about 12 hr apart. If patient vomits or a dose is missed, omit and take next dose at usual time. Advise patient to read  Patient Information  before starting therapy and with each Rx refill incase of changes.
  • Inform patient of potential for severe diarrhea and to notify health care professional if a change in bowel movements or severe diarrhea occurs. May lead to loss of too much body fluids (dehydration), low blood pressure, kidney problems, and death.
  • Advise patient to notify health care professional if signs and symptoms of liver problems (itching, yellowing of skin or eyes, dark or brown urine, pain in upper right side of abdomen, feel very tired, decreased appetite, bleeding or bruising more easily than normal) occur.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for at least 1 wk after last dose. Advise females of reproductive potential to avoid breastfeeding for at least 1 wk after last dose. Advise patient to notify health care professional immediately if pregnancy is suspected or planned or if breastfeeding. May impair female and male fertility.
  • Emphasize the importance of lab tests every 3 wk to monitor for liver problems.

Evaluation/Desired Outcomes

  • Improved survival and progression-free survival in metastatic breast cancer.
  • Decreased spread of colorectal cancer.