tucatinib

General

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).

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.

Pharmacokinetics

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

Distribution: Extensively distributed to extravascular tissues.

Metabolism and Excretion: Primarily metabolized by liver via CYP2C8 isoenzyme, and to a lesser extent by CYP3A4. 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 (CCr <30 mL/min)
  • OB:   Pregnancy (may cause fetal harm);
  •  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

CNS: headache

Derm: palmar-plantar erythrodysesthesia, rash

EENT: epistaxis

F and E: hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia

GI: DIARRHEA, HEPATOTOXICITY, abdominal pain, hyperbilirubinemia, nausea, stomatitis, vomiting

GU: ↑ serum creatinine, ↓ fertility

Hemat: anemia

Metabolic: ↓ appetite, ↓ weight

MS: arthralgia

Neuro: peripheral neuropathy

Misc: fatigue

* 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 be 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.

Monitor ALT, AST, and bilirubin before to starting tucatinib, every 3 wk during therapy, and as clinically indicated.  If Grade 2 bilirubin (>1.5 to 3 × ULN) occurs:  hold tucatinib until recovery to ≤ Grade 1, then resume at the same dose level.  If Grade 3 ALT or AST (> 5–20 × ULN) OR Grade 3 bilirubin (> 3–10 × ULN) occurs: hold tucatinib until recovery to ≤ Grade 1, then resume at the next lower dose level.  If Grade 4 ALT or AST (> 20 × ULN) OR Grade 4 bilirubin (> 10 × ULN) occurs: permanently discontinue tucatinib.  If ALT or AST > 3 × ULN AND bilirubin > 2 × ULN: permanently discontinue tucatinib.

  • May cause decreased hemoglobin, phosphate, magnesium, potassium, and sodium and increased creatinine.

Implementation

  • Tucatinib is taken with other agents.
  • 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 patient to avoid breastfeeding for at least 1 wk after last dose. Advise patient to notify health care professional immediately if pregnancy is suspected. 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.

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