TUCATINIB Drug Interactions: What You Need to Know

INTERACTIONS

• Strong CYP3A Inducers or Moderate CYP2C8 Inducers : Avoid concomitant use. ( 7.1 )
• Strong CYP2C8 Inhibitors : Avoid concomitant use; reduce TUKYSA dose if concomitant use cannot be avoided. ( 2.4 , 7.1 )
• CYP3A Substrates : Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.2 )
• P-gp Substrates : Consider reducing the dose of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.2 )

7.1 Effects of Other Drugs on TUKYSA Table 7 summarizes the effect of other drugs on TUKYSA.

Table

7: Drug Interactions that Affect TUKYSA Strong CYP3A Inducers or Moderate CYP2C8 Inducers Clinical Impact Concomitant use of TUKYSA with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may reduce TUKYSA activity.

Management

Avoid concomitant use of TUKYSA with a strong CYP3A inducer or a moderate CYP2C8 inducer. Strong or Moderate CYP2C8 Inhibitors Clinical Impact Concomitant use of TUKYSA with a strong CYP2C8 inhibitor increased tucatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of TUKYSA toxicity.

Management

Avoid concomitant use of TUKYSA with a strong CYP2C8 inhibitor. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.

7.2 Effects of TUKYSA on Other Drugs Table 8 summarizes the effect of TUKYSA on other drugs.

Table

8: TUKYSA Drug Interactions that Affect Other Drugs CYP3A Substrates Clinical Impact Concomitant use of TUKYSA with a CYP3A substrate increased the plasma concentrations of CYP3A substrate [see Clinical Pharmacology (12.3) ] , which may increase the toxicity associated with a CYP3A substrate.

Management

Avoid concomitant use of TUKYSA with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling. P-glycoprotein (P-gp)

Substrates Clinical Impact

Concomitant use of TUKYSA with a P-gp substrate increased the plasma concentrations of P-gp substrate [see Clinical Pharmacology (12.3) ] , which may increase the toxicity associated with a P-gp substrate.

Management

Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

None. None. ( 4 )

AND PRECAUTIONS

• Diarrhea : Severe diarrhea, including dehydration, acute kidney injury, and death, has been reported. Administer antidiarrheal treatment as clinically indicated. Interrupt dose, then dose reduce, or permanently discontinue TUKYSA based on severity. ( 2.2 , 5.1 )
• Hepatotoxicity : Severe hepatotoxicity has been reported on TUKYSA. Monitor ALT, AST and bilirubin prior to starting TUKYSA, every 3 weeks during treatment and as clinically indicated. Interrupt dose, then dose reduce, or permanently discontinue TUKYSA based on severity. ( 2.2 , 5.2 )
• Embryo-Fetal Toxicity : TUKYSA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) Also, refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.

5.1 Diarrhea TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . TUKYSA with trastuzumab and capecitabine In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 0.5% with Grade 4 diarrhea and 12% with Grade 3 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. TUKYSA with trastuzumab In MOUNTAINEER, diarrhea occurred in 64% of patients, including Grade 3 (3.5%), Grade 2 (10%), and Grade 1 (50%).

5.2 Hepatotoxicity TUKYSA can cause severe hepatotoxicity <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . TUKYSA with trastuzumab and capecitabine In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase &gt; 5 × ULN, 6% had an AST increase &gt; 5 × ULN, and 1.5% had a bilirubin increase &gt; 3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients. TUKYSA with trastuzumab In MOUNTAINEER, 6% of patients had a bilirubin increase &gt; 3 × ULN (Grade ≥3), 6% had an AST increase &gt; 5 × ULN, and 4.7% had an ALT increase &gt; 5 × ULN. Hepatotoxicity led to dose reduction of TUKYSA in 3.5% of patients and discontinuation of TUKYSA in 2.3% of patients.

5.3 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3 )]</span> . TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.