Tucatinib is an oral tyrosine kinase inhibitor of HER2. It is indicated, in combination with trastuzumab and capecitabine, for treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. It is also indicated in combination with trastuzumab for the treatment of unresectable or metastatic HER2-positive, RAS wild-type colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Severe diarrhea and hepatotoxicity have been reported. Monitor liver function tests during therapy. Advise patients to contact their health care provider if diarrhea occurs.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Tucatinib tablets should be taken with or without food at approximately 12 hours apart and at the same time every day.
-Swallow tablets whole; do not chew, crush, or split.
-If the patient vomits or a dose is missed, do not replace the dose. Resume tucatinib with the next scheduled dose.
Diarrhea resulting in dehydration, hypotension, acute kidney injury, and death can occur with tucatinib treatment. Prophylactic use of antidiarrheal treatment was not required on the HER2CLIMB trial, in which 81% (grade 3, 12%; grade 4, 0.5%) of breast cancer patients treated with tucatinib in combination with capecitabine and trastuzumab developed diarrhea compared with 53% (grade 3 or 4, 9%) of those who received placebo plus capecitabine and trastuzumab, contributing to death in the two patients with grade 4 diarrhea who received tucatinib. The incidence of diarrhea was 64% (grade 3, 3.5%) of patients with advanced colorectal cancer treated with tucatinib plus trastuzumab. The median time to onset of first episode of diarrhea was 12 days in the HER2CLIMB trial; the median time to resolution was 8 days. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated and rule out other causes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of diarrhea.
Elevated hepatic enzymes including increased ALT (46%; grade 3 or 4, 4.8%), increased AST (33%; grade 3 or 4, 5.9%), and increase alkaline phosphatase (25%; grade 3, 1.2%) occurred in patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial; hyperbilirubinemia occurred in 28% (grade 3 or 4, 5.9%) of these patients. Hepatotoxicity has also been reported in patients treated with tucatinib, occurring in 42% (grade 3 or 4, 9.2%) of patients treated with tucatinib plus capecitabine and trastuzumab compared with 24% (grade 3 or 4, 3.6%) of patients who received placebo plus capecitabine and trastuzumab in a randomized clinical trial; hyperbilirubinemia (47% vs. 30%; grade 3 or higher, 1.5% vs. 3.1%), increased ALT (46% vs. 27%; grade 3 or higher, 8% vs. 0.5%), increased AST (43% vs. 25%; grade 3 or higher, 6% vs. 1%), and increased alkaline phosphatase (26% vs. 17%; grade 3 or higher, 0.5% vs. 0%) each occurred more often in the tucatinib arm compared with the placebo arm in this study. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if hepatotoxicity occurs.
Nausea occurred in 35% of patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial; additional gastrointestinal (GI) adverse reactions included vomiting (16%), abdominal pain (21%; grade 3 or 4, 2.3%), and constipation (14%; grade 3 or 4, 1.2%). Serious cases of GI obstruction (7%) and rectal perforation (2.3%) were also reported. Nausea (58% vs. 44%; grade 3, 3.7% vs. 3%) and vomiting (36% vs. 25%; grade 3, 3% vs. 3.6%) occurred more often in patients treated with tucatinib plus capecitabine and trastuzumab compared with those who received placebo plus capecitabine and trastuzumab in a randomized clinical trial; serious cases of abdominal pain were also reported in 2% of these patients.
Oropharyngeal pain (5%), oral dysesthesia (1%), and stomatitis (1%) were reported in patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial. Stomatitis (including oropharyngeal pain, oral ulceration, lip ulceration, glossodynia, oral dysesthesia, and aphthous ulcer) occurred in 32% (grade 3, 2.5%) of patients treated with tucatinib plus capecitabine and trastuzumab compared with 21% (grade 3, 0.5%) of those who received placebo plus capecitabine and trastuzumab in a randomized clinical trial.
Rash (including maculopapular rash, acneiform rash, erythema, pustular rash, erythematous rash, exfoliative dermatitis, urticaria, allergic dermatitis, palmar erythema, and plantar erythema) occurred in 20% to 37% (grade 3, 0.7% or less) of patients treated with tucatinib plus trastuzumab (with or without capecitabine) in 2 clinical trials. Palmar-plantar erythrodysesthesia (hand and foot syndrome) occurred in 63% (grade 3, 13%) of patients who received tucatinib, trastuzumab, and capecitabine versus 53% (grade 3, 9%) of those who received placebo plus capecitabine and trastuzumab in one of these trials.
Decreased appetite/anorexia (19% to 25%; grade 3, 0% or less) and weight loss (7% to 13%; grade 3, 1% or less) occurred in patients treated with tucatinib and trastuzumab (with or without capecitabine) in 2 clinical trials.
Arthralgia occurred in 15% to 16% (grade 3, 0.5% to 1.2%) of patients treated with tucatinib and trastuzumab (with or without capecitabine) in 2 clinical trials. Back pain (17%; grade 3 or 4, 2.3%) and myalgia (13%) were also reported in patients treated with tucatinib plus trastuzumab.
Peripheral neuropathy (sensory and motor) occurred in 13% (grade 3, 0.5%) of patients with metastatic breast cancer treated with tucatinib plus capecitabine and trastuzumab compared with 7% (grade 3, 1%) of those who received placebo plus capecitabine and trastuzumab in a randomized clinical trial.
Epistaxis occurred in 7% to 12% of patients treated with tucatinib and trastuzumab (with or without capecitabine) in 2 clinical trials.
Electrolyte abnormalities including hypophosphatemia, hypomagnesemia, hypokalemia, and hyponatremia have been reported in patients treated with tucatinib. Decreases from baseline in sodium (20%; grade 3, 6%) and potassium (16%; grade 3, 1.2%) were reported in patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial. In a randomized clinical trial, patients treated with tucatinib plus trastuzumab and capecitabine experienced higher rates of decreased phosphate (57% vs. 45%; grade 3 or higher, 8% vs. 7%), decreased magnesium (40% vs. 25%; grade 3 or higher, 0.8% vs. 0.5%), decreased potassium (33% vs. 6%), and decreased sodium (28% vs. 23%; grade 3 or higher, 2.5% vs. 2%) compared with those receiving placebo plus capecitabine and trastuzumab. Increased creatinine can occur with tucatinib therapy due to inhibition of renal tubular transport of creatinine via OCT2 and MATE1 and was reported in 58% of patients treated with tucatinib plus trastuzumab in a nonrandomized trial. Increased creatinine occurred in 14% to 33% of patients treated with tucatinib plus capecitabine and trastuzumab compared with vs. 1.5% to 6% of those who received placebo plus capecitabine and trastuzumab in a randomized clinical trial; glomerular function was not affected. The mean increased in serum creatinine was 32% within the first 21 days of treatment; increases persisted throughout treatment and were reversible upon completion in 87% of patients. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
Decreased hemoglobin (46%; grade 3, 3.5%) and anemia (10%) occurred in patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial. In another randomized clinical trial where patients were treated with capecitabine and trastuzumab with either tucatinib or placebo, decreased hemoglobin occurred in 59% versus 51% (grade 3 or higher, 3.3% vs. 1.5%) and anemia occurred in 21% versus 13% (grade 3, 3.7% vs. 2.5%) of patients, respectively. Decreases from baseline in lymphocytes (lymphopenia) (39%; grade 3, 12%), leukocytes (leukopenia) (22%), and platelets (thrombocytopenia) (15%) were also reported in patients who received tucatinib plus trastuzumab.
Seizures occurred in 2% of patients with metastatic breast cancer treated with tucatinib plus capecitabine and trastuzumab in a randomized clinical trial.
Increases from baseline in glucose (hyperglycemia) occurred in 56% of patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial (grade 3, 2.4%).
Increases from baseline in albumin (hypoalbuminemia) occurred in 24% of patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial (grade 3, 1.2 %).
Fatigue occurred in 44% of patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial (grade 3 or 4, 2.3 %).
Fever (20%) and chills (19%; grade 3 or 4, 1.2%) were reported in patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial.
Hypertension occurred in 17% of patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial (grade 3 or 4, 7%).
Cough (16%) and dyspnea (14%) were reported in patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial.
Anxiety occurred in 10% of patients treated with tucatinib plus trastuzumab in a nonrandomized clinical trial.
Use tucatinib with caution in patients with a history of hepatic disease; tucatinib can cause severe hepatotoxicity. A dose reduction is necessary for patients with severe hepatic impairment (Child-Pugh C). Monitor liver function tests (ALT, AST, and bilirubin) prior to starting tucatinib therapy, every 3 weeks during treatment, and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if hepatotoxicity occurs.
Treatment with tucatinib can cause increases in serum creatinine in up to a third of patients that persist throughout treatment and are reversible upon completion of therapy. This may give the appearance of renal impairment, however, the increases are due to inhibition of renal tubular transport of creatinine via OCT2 and MATE1 and do not affect glomerular function. The mean increase in serum creatinine was 32% within the first 21 days of treatment with tucatinib. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
Pregnancy should be avoided by females of reproductive potential during tucatinib treatment and for 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, tucatinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving tucatinib should be apprised of the potential hazard to the fetus. In pilot embryo-fetal development studies, oral administration of tucatinib at approximately 3.5 times the human exposure at the recommended dose based on AUC resulted in maternal toxicity (weight loss, reduced weight gain, low food consumption) and fetal toxicity including a reduced number of live fetuses, decreased fetal weight, increase in skeletal variations and incomplete ossification. In rabbits, oral administration of tucatinib at approximately 1.3 times the human exposure at the recommended dose based on AUC resulted in increased resorptions, decreased percentages of live fetuses, and skeletal, visceral, and external malformations (domed head, brain dilation, incomplete ossification of frontal and parietal bones, and a hole in the parietal bone).
Counsel patients about the reproductive risk and contraception requirements during tucatinib treatment. Tucatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 1 week after treatment with tucatinib; due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should undergo the same precautions. Females of reproductive potential should undergo pregnancy testing prior to initiation of tucatinib. Women who become pregnant while receiving tucatinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of tucatinib on human fertility, male and female infertility may occur.
Due to the potential for serious adverse reactions in nursing infants from tucatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether tucatinib is present in human milk, although many drugs are excreted in human milk.
For the treatment of breast cancer:
NOTE: Tucatinib is designated by the FDA as an orphan drug for the treatment of breast cancer patients with brain metastases.
-for the treatment of advanced unresectable or metastatic HER2-positive breast cancer in patients who have received at least one prior anti-HER2-based regimen in the metastatic setting, in combination with trastuzumab and capecitabine:
Oral dosage:
Adults: 300 mg PO twice daily until disease progression or unacceptable toxicity. Administer in combination with trastuzumab (8 mg/kg IV over 90 minutes on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV over 30 minutes repeated every 21 days) and capecitabine (1,000 mg/m2 PO twice daily within 30 minutes after a meal on days 1 to 14 of each 21-day cycle) until disease progression or unacceptable toxicity; tucatinib and capecitabine can be taken at the same time. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The addition of tucatinib to trastuzumab and capecitabine significantly improved median progression-free survival (PFS) (7.8 months vs. 5.6 months) and overall survival (21.9 months vs. 17.4 months) compared with placebo plus trastuzumab and capecitabine in patients with HER2-positive, unresectable locally advanced or metastatic breast cancer after prior HER2 treatment in a randomized, double-blind clinical trial (HER2CLIMB); all patients had received prior trastuzumab and ado-trastuzumab emtansine and all but 2 patients had prior pertuzumab. The confirmed objective response rate was also significantly improved with the addition of tucatinib (40.6% vs. 22.8%; complete response, 3% vs. 2%) for a median duration of 8.3 months versus 6.3 months, respectively. Patients with brain metastases were eligible for inclusion in the HER2CLIMB study as long as they were neurologically stable and did not require immediate radiation or surgery; patients with leptomeningeal disease were excluded. The median PFS in patients with brain metastases was similar to the overall population (7.6 months vs. 5.4 months).
For the treatment of colorectal cancer:
-for the treatment of 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:
NOTE: Tucatinib has been designated by the FDA as an orphan drug for the treatment of HER2-positive colorectal cancer.
NOTE: Select patients based on the presence of HER2 overexpression or gene amplification and RAS wild-type. An FDA-approved test for the detection of HER2 protein overexpression or gene amplification in patients with unresectable or metastatic colorectal cancer is not currently available. Information on FDA-approved tests for the detection of RAS mutations is available at www.fda.gov/CompanionDiagnostics.
Oral dosage:
Adults: 300 mg PO twice daily until disease progression or unacceptable toxicity. Administer in combination with trastuzumab (8 mg/kg IV on day 1 of cycle 1, followed 3 weeks later by 6 mg/kg IV repeated every 21 days) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, noncomparative trial (MOUNTAINEER; n = 84), treatment with tucatinib plus trastuzumab resulted in an overall response rate of 38% (complete response, 3%) for a median duration of 12.4 months in patients with HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer previously treated with a fluoropyrimidine, oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody; the duration of response was at least 6 months in 81% of patients, and at least 12 months in 34% of patients.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Interrupt tucatinib therapy per specific instructions below. Restart tucatinib as appropriate at the following reduced doses (refer to capecitabine and trastuzumab prescribing information for dose modifications of those drugs):
-First dose reduction: 250 mg PO twice daily.
-Second dose reduction: 200 mg PO twice daily.
-Third dose reduction: 150 mg PO twice daily.
-Further dose reduction: Permanently discontinue tucatinib in patients unable to tolerate 150 mg PO twice daily.
Diarrhea
-Grade 3, not on antidiarrheal treatment: Hold tucatinib therapy and initiate or intensify appropriate medical therapy. When diarrhea recovers to grade 1 or less, resume tucatinib treatment at the same dose level.
-Grade 3, on antidiarrheal treatment: Hold tucatinib therapy and initiate or intensify appropriate medical therapy. When diarrhea recovers to grade 1 or less, resume tucatinib treatment at the next lower dose level.
-Grade 4: Permanently discontinue tucatinib therapy.
Other Adverse Reactions
-Grade 3: Hold tucatinib therapy. When toxicity recovers to grade 1 or less, resume tucatinib treatment at the next lower dose level.
-Grade 4: Permanently discontinue tucatinib therapy.
Maximum Dosage Limits:
-Adults
300 mg PO twice daily.
-Geriatric
300 mg PO twice daily.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment:
-Mild and moderate hepatic impairment (Child-Pugh A and B): No dosage adjustments are recommended.
-Severe hepatic impairment (Child-Pugh C): Reduce the dose of tucatinib to 200 mg PO twice daily.
Treatment-Related Hepatotoxicity:
-Grade 2 hyperbilirubinemia (total bilirubin 1.5 to 3 times the upper limit of normal [ULN]): Hold tucatinib therapy. When bilirubin recovers to grade 1 or less, resume tucatinib treatment at the same dose level.
-Grade 3 hyperbilirubinemia (total bilirubin 3.1 to 10 times ULN) or grade 3 transaminitis (ALT/AST 5.1 to 20 times ULN): Hold tucatinib therapy. When the bilirubin and ALT/AST recover to grade 1 or less, resume tucatinib treatment at the next lower dose level.
-Grade 4 hyperbilirubinemia (total bilirubin greater than 10 times ULN) or grade 4 transaminitis (ALT/AST greater than 20 times ULN): Permanently discontinue tucatinib therapy.
-ALT/AST greater than 3 times ULN with total bilirubin greater than 2 times ULN: Permanently discontinue tucatinib therapy.
Patients with Renal Impairment Dosing
-Mild or moderate renal impairment (CrCl 30 to 89 mL/min): No dosage adjustment is recommended.
-Severe renal impairment (CrCl less than 30 mL/min): The use of tucatinib in combination with capecitabine and trastuzumab is not recommended because capecitabine is contraindicated in patients with severe renal impairment.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Abemaciclib: (Major) If coadministration with tucatinib is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If tucatinib is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of tucatinib. Abemaciclib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and tucatinib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with tucatinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Tucatinib is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If tucatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like tucatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tucatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of tucatinib. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of tucatinib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until tucatinib has cleared from the circulation (approximately 3 half-lives of tucatinib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; tucatinib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of tucatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of tucatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and tucatinib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If tucatinib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Contraindicated) Coadministration of alfuzosin and tucatinib is contraindicated due to increased alfuzosin exposure. Alfuzosin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. When coadministered with another strong CYP3A4 inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold.
Aliskiren: (Moderate) Coadministration of aliskiren and tucatinib may increase the exposure of aliskiren. Monitor for adverse effects, such as decreased blood pressure, during coadministration. Aliskiren is a substrate of CYP3A4 and P-glycoprotein (P-gp); tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of aliskiren and tucatinib may increase the exposure of aliskiren. Monitor for adverse effects, such as decreased blood pressure, during coadministration. Aliskiren is a substrate of CYP3A4 and P-glycoprotein (P-gp); tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with tucatinib is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and tucatinib should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alosetron: (Moderate) Concomitant use of alosetron with tucatinib may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; tucatinib is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alprazolam: (Contraindicated) Coadministration of tucatinib and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with tucatinib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Amiodarone: (Major) Avoid concomitant use of amiodarone and tucatinib due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Atorvastatin: (Major) Coadministration of atorvastatin with tucatinib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Tucatinib is a strong CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Apalutamide: (Major) Avoid coadministration of tucatinib and apalutamide due to the risk of decreased tucatinib exposure which may reduce its efficacy. Additionally, apalutamide-related adverse reactions may increase. Tucatinib is a CYP3A4 and CYP2C8 substrate and a strong CYP3A4 inhibitor; apalutamide is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Apixaban: (Major) Reduce the apixaban dose by 50% when administered with tucatinib. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid coadministration. Concomitant administration of apixaban and tucatinib may result in increased exposure to apixaban and an increase in the risk of bleeding. Apixaban is a P-gp and CYP3A4 substrate; tucatinib is a P-gp and strong CYP3A4 inhibitor. In a drug interaction study, administration of another combined P-gp/strong CYP3A4 inhibitor increased the apixaban AUC by 2-fold.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of tucatinib and aprepitant, fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Aprepitant is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Administration of a strong CYP3A4 inhibitor increased the aprepitant AUC and mean terminal half-life by approximately 5-fold and 3-fold, respectively.
Aripiprazole: (Major) Recommendations for managing aripiprazole and tucatinib vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; tucatinib is a strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and tucatinib vary by aripiprazole dosage form and CYP2D6 metabolizer status. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; tucatinib is a strong CYP3A inhibitor.
Artemether; Lumefantrine: (Moderate) Due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, tucatinib should be used cautiously with artemether; lumefantrine. No dosage adjustment of artemether; lumefantrine is necessary. Tucatinib is a strong inhibitor of CYP3A4 and artemether is a substrate of this isoenzyme. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine. (Moderate) Due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, tucatinib should be used cautiously with artemether; lumefantrine. No dosage adjustment of artemether; lumefantrine is necessary. Tucatinib is a strong inhibitor of CYP3A4 and lumefantrine is a substrate of this isoenzyme. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with tucatinib is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Aspirin, ASA; Omeprazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like tucatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tucatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir; Cobicistat: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with tucatinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Atogepant: (Major) Avoid use of atogepant and tucatinib when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with tucatinib. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and tucatinib is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atorvastatin: (Major) Coadministration of atorvastatin with tucatinib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Tucatinib is a strong CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of tucatinib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Do not use avanafil in patients receiving tucatinib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Avapritinib: (Major) Avoid coadministration of avapritinib with tucatinib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with tucatinib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after tucatinib is discontinued. Axitinib is a CYP3A4/5 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and tucatinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Bedaquiline: (Major) Concurrent use of bedaquiline and tucatinib should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like tucatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If tucatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving tucatinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving tucatinib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; tucatinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2- to 3-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with tucatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of tucatinib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Bosentan: (Moderate) Use caution if coadministration of tucatinib with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both tucatinib and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A4 and CYP2C9 substrate; tucatinib is a strong CYP3A4 inhibitor.
Bosutinib: (Major) Avoid concomitant use of bosutinib and tucatinib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with tucatinib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Brexpiprazole: (Major) Reduce the brexpiprazole dose to half the usual dose if coadministered with tucatinib. Administer one quarter of the usual brexpiprazole dose if the patient is also receiving a strong or moderate CYP2D6 inhibitor or is a known poor metabolizer of CYP2D6. If tucatinib is discontinued, adjust the brexpiprazole dosage to its original level. Brexpiprazole is a CYP3A4 and CYP2D6 substrate; tucatinib is a strong CYP3A4 inhibitor. Concomitant use of strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Brigatinib: (Major) Avoid coadministration of brigatinib with tucatinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of tucatinib, resume the brigatinib dose that was tolerated prior to initiation of tucatinib. Brigatinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with tucatinib ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; tucatinib is a strong inhibitor of CYP3A4.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and tucatinib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and tucatinib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and tucatinib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with tucatinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and tucatinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when tucatinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping tucatinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If tucatinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and tucatinib is a CYP3A4 inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and tucatinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when tucatinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping tucatinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If tucatinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and tucatinib is a CYP3A4 inhibitor.
Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with tucatinib. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering tucatinib with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with tucatinib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and tucatinib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with tucatinib 2 to 3 days after discontinuation of tucatinib. Cabozantinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Capivasertib: (Major) Avoid coadministration of capivasertib with tucatinib due to increased capivasertib exposure which may increase the risk for capivasertib-related adverse effects. If coadministration is necessary, reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off; monitor for adverse reactions. Capivasertib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.7-fold.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with tucatinib is necessary. Capmatinib is a CYP3A substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
Carbamazepine: (Major) Avoid coadministration of tucatinib and carbamazepine due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Cariprazine: (Major) The dose of cariprazine should be reduced in patients also receiving tucatinib. When tucatinib is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on tucatinib, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. When tucatinib is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. Tucatinib is a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with tucatinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of tucatinib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Ceritinib: (Major) Avoid concomitant use of ceritinib with tucatinib due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After tucatinib is discontinued, resume the dose of ceritinib taken prior to initiating tucatinib. Ceritinib is a CYP3A substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chlordiazepoxide: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with tucatinib is necessary; adjust the dose of chlordiazepoxide if necessary. Tucatinib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with tucatinib is necessary; adjust the dose of chlordiazepoxide if necessary. Tucatinib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Chlordiazepoxide; Clidinium: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with tucatinib is necessary; adjust the dose of chlordiazepoxide if necessary. Tucatinib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If tucatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with tucatinib and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of tucatinib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of tucatinib as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; tucatinib is a strong inhibitor of CYP3A4.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with tucatinib; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Clopidogrel: (Moderate) Closely monitor for tucatinib-related adverse reactions if coadministration with clopidogrel is necessary due to the risk of increased tucatinib exposure. Tucatinib is a CYP2C8 substrate and clopidogrel is a moderate CYP2C8 inhibitor.
Clorazepate: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of clorazepate with tucatinib is necessary. Concurrent use may increase clorazepate exposure. Clorazepate is a prodrug whose active metabolite (N-desmethyldiazepam) is a CYP3A4 substrate. Tucatinib is a strong CYP3A4 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with tucatinib and monitor for adverse reactions. If tucatinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4; tucatinib is a strong CYP3A4 inhibitor.
Cobicistat: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with tucatinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Cobimetinib: (Major) Avoid coadministration of tucatinib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Codeine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with tucatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of tucatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If tucatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Tucatinib is a strong inhibitor of CYP3A4.
Colchicine: (Major) Avoid concomitant use of colchicine and tucatinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and tucatinib is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Conivaptan: (Contraindicated) Coadministration of conivaptan and tucatinib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the exposure of oral conivaptan by 11-fold. The effect on the pharmacokinetics of intravenous conivaptan was not evaluated.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of tucatinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Tucatinib is a strong CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and tucatinib if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; tucatinib is a strong CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of crizotinib and tucatinib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with tucatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with tucatinib is necessary in patients with CrCL greater than 50 mL/minute. Avoid coadministration in patients with CrCL less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein substrate and tucatinib is a P-gp inhibitor.
Dabrafenib: (Major) Avoid coadministration of dabrafenib and tucatinib due to increased dabrafenib exposure. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Dabrafenib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%.
Dapagliflozin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with tucatinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Daridorexant: (Major) Avoid concomitant use of daridorexant and tucatinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with tucatinib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor.
Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with tucatinib is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Tucatinib is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir: (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with tucatinib. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Darunavir; Cobicistat: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with tucatinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with tucatinib. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with tucatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. (Moderate) Monitor for cobicistat-related adverse effects if coadministered with tucatinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with tucatinib. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Dasatinib: (Major) Avoid coadministration of dasatinib and tucatinib due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to tucatinib with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of tucatinib in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue tucatinib or stop dasatinib until tucatinib is discontinued. Allow a washout of approximately 1 week after tucatinib is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
Deferasirox: (Moderate) Closely monitor for tucatinib-related adverse reactions if coadministration with deferasirox is necessary due to the risk of increased tucatinib exposure. Tucatinib is a CYP2C8 substrate and deferasirox is a moderate CYP2C8 inhibitor.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with tucatinib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; tucatinib is a strong inhibitor of CYP3A4. Administration of deflazacort with another strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of tucatinib with dexamethasone is necessary, due to increased dexamethasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Consider the use of corticosteroids such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, especially for long-term use. Tucatinib is a strong CYP3A inhibitor and dexamethasone is primarily metabolized by CYP3A. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexlansoprazole: (Minor) The plasma concentrations of dexlansoprazole may be elevated when administered concurrently with tucatinib. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Dexlansoprazole is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor.
Dextromethorphan; Quinidine: (Moderate) Monitor for quinidine-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase quinidine exposure. Quinidine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with tucatinib is necessary; decrease the dose of diazepam if necessary. Concurrent use may increase exposure of diazepam. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Tucatinib is a strong CYP3A4 inhibitor.
Digoxin: (Moderate) Monitor for an increase in digoxin-related adverse reactions if coadministration with tucatinib is necessary; monitor digoxin concentrations as clinically appropriate. Concurrent use may increase digoxin exposure. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and tucatinib is a P-gp inhibitor. Coadministration with tucatinib increased digoxin exposure by 50%.
Dihydroergotamine: (Contraindicated) Concomitant use of ergotamine with tucatinib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with tucatinib is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with tucatinib is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with other strong CYP3A4 inhibitors.
Docetaxel: (Major) Avoid coadministration of docetaxel with tucatinib if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with tucatinib is necessary as concurrent use may increase dofetilide exposure. Tucatinib is a strong CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Donepezil: (Moderate) Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is recommended during coadministration of tucatinib. The plasma concentrations of donepezil may be elevated when administered concurrently with tucatinib. Donepezil is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Donepezil; Memantine: (Moderate) Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is recommended during coadministration of tucatinib. The plasma concentrations of donepezil may be elevated when administered concurrently with tucatinib. Donepezil is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Doravirine: (Minor) Coadministration of doravirine and tucatinib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; tucatinib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. (Minor) Coadministration of doravirine and tucatinib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; tucatinib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with tucatinib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with tucatinib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with tucatinib. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A4 substrate; tucatinib is a strong CYP3A inhibitor.
Dronedarone: (Contraindicated) Coadministration of dronedarone with tucatinib is contraindicated due to the potential for increased dronedarone exposure and QT prolongation. Dronedarone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Drospirenone: (Moderate) Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and tucatinib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Tucatinib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations.
Drospirenone; Estetrol: (Moderate) Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and tucatinib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Tucatinib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations.
Drospirenone; Estradiol: (Moderate) Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and tucatinib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Tucatinib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations.
Drospirenone; Ethinyl Estradiol: (Moderate) Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and tucatinib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Tucatinib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and tucatinib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Tucatinib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Dutasteride: (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with tucatinib is necessary. Dutasteride is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and tucatinib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4, and strong inhibitors of CYP3A4, such as tucatinib, are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with tucatinib is necessary. Dutasteride is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with tucatinib. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; tucatinib is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as tucatinib.
Edoxaban: (Major) If coadministered with tucatinib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with tucatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of tucatinib. Increased concentrations of edoxaban may occur during concomitant use of tucatinib; monitor for increased adverse effects of edoxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Elacestrant: (Major) Avoid concomitant use of elacestrant and tucatinib due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and tucatinib for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and tucatinib to 6 months. Coadministration may increase elagolix exposure. Elagolix is a CYP3A4 substrate; tucatinib is a strong inhibitor of CYP3A4. Coadministration of elagolix with another strong CYP3A4 inhibitor increased the AUC of elagolix by 120%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and tucatinib for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and tucatinib to 6 months. Coadministration may increase elagolix exposure. Elagolix is a CYP3A4 substrate; tucatinib is a strong inhibitor of CYP3A4. Coadministration of elagolix with another strong CYP3A4 inhibitor increased the AUC of elagolix by 120%.
Elbasvir; Grazoprevir: (Moderate) Monitor for an increase in elbasvir-related adverse reactions if coadministration with tucatinib is necessary. Elbasvir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased elbasvir exposure by 3-fold. (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase grazoprevir exposure. Grazoprevir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold.
Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of tucatinib due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) If tucatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with tucatinib; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; tucatinib is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with tucatinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of tucatinib and eliglustat is contraindicated. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both tucatinib and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Tucatinib is a strong CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors such as tucatinib increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with tucatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. (Moderate) Monitor for cobicistat-related adverse effects if coadministered with tucatinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. (Moderate) Monitor for cobicistat-related adverse effects if coadministered with tucatinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Coadministration of tenofovir alafenamide with tucatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with tucatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of tucatinib and encorafenib due to the risk of decreased tucatinib exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Tucatinib is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tucatinib exposure by 50%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with tucatinib is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; tucatinib is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid coadministration of entrectinib with tucatinib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Enzalutamide: (Major) Avoid coadministration of tucatinib and enzalutamide due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Eplerenone: (Contraindicated) Eplerenone is contraindicated for use with tucatinib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Tucatinib is a strong CYP3A inhibitor; eplerenone is a sensitive CYP3A substrate. Another strong CYP3A inhibitor increased serum eplerenone concentrations by roughly 5-fold.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and tucatinib due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased erdafitinib overall exposure by 134%.
Ergotamine: (Contraindicated) Concomitant use of ergotamine with tucatinib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Ergotamine; Caffeine: (Contraindicated) Concomitant use of ergotamine with tucatinib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Erlotinib: (Major) Avoid coadministration of erlotinib with tucatinib if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Estazolam: (Moderate) Monitor for estazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with tucatinib is necessary. Tucatinib is a strong CYP3A4 inhibitor and estazolam is primarily metabolized by CYP3A4. In vivo drug-drug interaction studies were not conducted between estazolam and inhibitors of CYP3A.
Estradiol; Progesterone: (Moderate) Use caution if coadministration of tucatinib with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Tucatinib is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Eszopiclone: (Major) The total dose of eszopiclone should not exceed 2 mg when administered with tucatinib. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased eszopiclone exposure by 2.2-fold.
Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with tucatinib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and tucatinib is a strong CYP3A4 inhibitor.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Etrasimod: (Major) Avoid concomitant use of etrasimod and tucatinib in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if coadministration with tucatinib is necessary. Etravirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased etravirine exposure by 1.42-fold.
Everolimus: (Major) Avoid coadministration of everolimus with tucatinib due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Tucatinib is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) Concurrent use of simvastatin and tucatinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Fedratinib: (Major) Avoid coadministration of fedratinib with tucatinib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If tucatinib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Moderate) Concurrent use of felodipine and tucatinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If tucatinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with tucatinib. Avoid use of fesoterodine and tucatinib in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Fexinidazole: (Major) Avoid concomitant use of fexinidazole and tucatinib and monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and tucatinib is a strong CYP3A inhibitor.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and tucatinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of tucatinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as tucatinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Finerenone: (Contraindicated) Concomitant use of finerenone and tucatinib is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors such as tucatinib is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of tucatinib, start flibanserin at least 2 weeks after the last dose of tucatinib. If initiating tucatinib following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating tucatinib therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with tucatinib is necessary; adjust the dose of flurazepam if necessary. Flurazepam is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and tucatinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with tucatinib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and tucatinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and tucatinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Caution is warranted when tucatinib is administered with vilanterol as there is a potential for elevated vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Vilanterol is a substrate of CYP3A4 and tucatinib is a strong CYP3A4 inhibitor.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and tucatinib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Caution is warranted when tucatinib is administered with vilanterol as there is a potential for elevated vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Vilanterol is a substrate of CYP3A4 and tucatinib is a strong CYP3A4 inhibitor.
Food: (Major) Advise patients to avoid cannabis use during tucatinib treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and tucatinib is a strong CYP3A inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with tucatinib is necessary, due to increased mometasone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Fosamprenavir: (Moderate) Monitor for increased toxicity of fosamprenavir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Fosphenytoin: (Major) Avoid coadministration of tucatinib and fosphenytoin due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Fostamatinib: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of tucatinib with fostamatinib is necessary. Fostamatinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to R406 (the major active metabolite of fostamatinib) by 102%.
Futibatinib: (Major) Avoid concurrent use of futibatinib and tucatinib. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; tucatinib is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with tucatinib is necessary. Gefitinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gemfibrozil: (Major) Avoid coadministration of tucatinib and gemfibrozil due to the risk of increased tucatinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of tucatinib to 100 mg twice daily. If gemfibrozil is discontinued, resume the original tucatinib dose after 3 elimination half-lives of gemfibrozil. Tucatinib is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with gemfibrozil increased tucatinib exposure by 3-fold.
Gilteritinib: (Major) Consider an alternative to tucatinib during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
Glasdegib: (Major) Consider an alternative to tucatinib during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and tucatinib as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-glycoprotein (P-gp) and tucatinib is a P-gp inhibitor. (Moderate) Caution is advised with coadministration of pibrentasvir and tucatinib as increased plasma concentrations of pibrentasvir may occur resulting in increased risk of pibrentasvir-related adverse events. Pibrentasvir is a substrate of P-glycoprotein (P-gp) and tucatinib is a P-gp inhibitor.
Granisetron: (Moderate) Monitor for increased granisetron-related adverse effects, such as gastrointestinal or CNS effects, if coadministration with tucatinib is necessary. Concurrent use may increase granisetron exposure. Granisetron is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Guanfacine: (Major) If coadministration of tucatinib with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for adverse effects including hypotension, drowsiness, lethargy, and bradycardia. If tucatinib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Tucatinib may significantly increase guanfacine plasma concentrations.
Haloperidol: (Moderate) Monitor for haloperidol-related adverse effects, including QT prolongation, if coadministered with tucatinib. Concurrent use may result in increased serum concentrations of haloperidol. Haloperidol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If tucatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If tucatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If tucatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with tucatinib. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and tucatinib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like tucatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tucatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Coadministration of idelalisib with tucatinib may increase idelalisib exposure; use alternative agents if possible. If concomitant use is required, monitor patients frequently for signs and symptoms of idelalisib-related adverse reactions (e.g., hepatotoxicity, diarrhea, neutropenia, and infection). Idelalisib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased idelalisib exposure by 1.8-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with tucatinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Tucatinib is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with tucatinib. If tucatinib is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Imatinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with tucatinib is necessary. Imatinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
Indacaterol; Glycopyrrolate: (Moderate) Monitor for indacaterol-related adverse effects, such as headache, nervousness, tremor, or cardiovascular effects, during coadministration with tucatinib. Concurrent use may increase plasma concentrations of indacaterol. Indacaterol is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration with other dual inhibitors of CYP3A4 and P-gp has increased exposure of indacaterol from 1.4- to 1.9- fold.
Indinavir: (Moderate) Coadministration of indinavir with tucatinib may result in increased plasma concentrations of indinavir, leading to an increase in indinavir-related adverse effects. Although specific recommendations are unavailable for use with tucatinib, a reduced indinavir dose of 600 mg PO every 8 hours is recommended when coadministered with other strong CYP3A4 inhibitors. Indinavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Infigratinib: (Major) Avoid concomitant use of infigratinib and tucatinib. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Irinotecan Liposomal: (Major) Avoid administration of tucatinib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Tucatinib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of tucatinib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Tucatinib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Isavuconazonium: (Contraindicated) Coadministration of isavuconazonium with tucatinib is contraindicated due to the risk of increased isavuconazole exposure. Isavuconazole is a sensitive substrate of CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased isavuconazole exposure by 422%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of tucatinib and rifampin due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and rifampin is a strong CYP3A4/moderate CYP2C8 inducer. Coadministration with rifampin decreased tucatinib exposure by 50%.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of tucatinib and rifampin due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and rifampin is a strong CYP3A4/moderate CYP2C8 inducer. Coadministration with rifampin decreased tucatinib exposure by 50%.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with tucatinib is necessary. Concomitant use may increase isradipine exposure. Tucatinib is a strong CYP3A4 inhibitor and isradipine is metabolized by CYP3A4.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with tucatinib as istradefylline exposure and adverse effects may increase. Tucatinib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Moderate) Monitor for itraconazole-related adverse reactions during coadministration with tucatinib; an itraconazole dose reduction may be necessary. Concurrent use may increase itraconazole exposure. Itraconazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ivabradine: (Contraindicated) Coadministration of tucatinib with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
Ivacaftor: (Major) If tucatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with tucatinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If tucatinib is discontinued, wait at least 5 half-lives of tucatinib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and tucatinib due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Major) Avoid tucatinib for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Lansoprazole: (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Lapatinib: (Major) Avoid coadministration of lapatinib with tucatinib due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If tucatinib is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with tucatinib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If tucatinib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of tucatinib. Larotrectinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Lefamulin: (Major) Avoid coadministration of tucatinib with oral lefamulin due to increased lefamulin exposure; tucatinib may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral lefamulin by 165%; the exposure to intravenous lefamulin was increased by 31%.
Leflunomide: (Moderate) Closely monitor for tucatinib-related adverse reactions if coadministration with leflunomide is necessary due to the risk of increased tucatinib exposure. Tucatinib is a CYP2C8 substrate and leflunomide is a moderate CYP2C8 inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and tucatinib as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong/moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and tucatinib due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Levoketoconazole: (Major) Avoid tucatinib for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with tucatinib is necessary. Levomilnacipran is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased levomilnacipran exposure by about 50%.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with tucatinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with tucatinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with tucatinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Lomitapide: (Contraindicated) Concomitant use of tucatinib and lomitapide is contraindicated; if treatment with tucatinib is unavoidable, lomitapide should be stopped during treatment. Tucatinib is a strong CYP3A4 inhibitor and lomitapide is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lomitapide exposure approximately 27-fold.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and tucatinib is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with tucatinib. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and tucatinib is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with tucatinib. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and tucatinib is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Moderate) Monitor for increased toxicity of ritonavir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of ritonavir. Ritonavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with tucatinib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If tucatinib is discontinued, resume the original dose of lorlatinib after 3 half-lives of tucatinib. Lorlatinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
Lovastatin: (Contraindicated) Coadministration of lovastatin and tucatinib is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tucatinib and lumacaftor; ivacaftor due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%. (Major) If tucatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tucatinib and lumacaftor; ivacaftor due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of tucatinib is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Coadministration of lurasidone with tucatinib is contraindicated due to increased plasma concentrations of lurasidone. Lurasidone is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lurasidone exposure by 9-fold.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and tucatinib due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macitentan: (Major) Avoid coadministration of macitentan with tucatinib due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
Macitentan; Tadalafil: (Major) Avoid coadministration of macitentan with tucatinib due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold. (Major) Avoid coadministration of tadalafil and tucatinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of tucatinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as tucatinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Maraviroc: (Major) Reduce the dose of maraviroc when coadministered with tucatinib; coadministration is contraindicated in patients with CrCl less than 30 mL/minute. Coadministration of maraviroc, a CYP3A/P-gp substrate, with tucatinib, a strong CYP3A4 inhibitor and P-gp inhibitor, may result in increased maraviroc concentrations. Maraviroc dosage adjustments are as follows when administered with tucatinib (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with tucatinib due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Medroxyprogesterone: (Moderate) Use caution if coadministration of tucatinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Tucatinib is a strong CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with tucatinib is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse reactions. Mefloquine is a substrate of CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of mefloquine by 79%.
Metformin; Repaglinide: (Major) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with tucatinib is necessary. Repaglinide is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
Metformin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with tucatinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A4; tucatinib is a strong CYP3A inhibitor. Concomitant use with tucatinib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methylergonovine: (Major) Avoid concomitant use of methylergonovine with tucatinib. Concomitant use may increase methylergonovine exposure and the risk for vasospasm which may lead to cerebral or peripheral ischemia. Methylergonovine is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Methylprednisolone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of methylprednisolone with tucatinib is necessary, due to increased methylprednisolone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Methylprednisolone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with tucatinib is necessary; a dose adjustment of midazolam may be necessary. Concurrent use may increase midazolam exposure. Midazolam is a sensitive CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and tucatinib due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Major) Caution is advised when administering tucatinib with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with tucatinib should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving tucatinib, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with tucatinib is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with tucatinib is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with tucatinib is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with tucatinib is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Mifepristone is a CYP3A4 substrate, a strong CYP3A4 inhibitor, and a moderate CYP2C8 inhibitor; tucatinib is a CYP2C8 substrate and strong CYP3A4 inhibitor.
Mirtazapine: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with tucatinib is necessary. Mirtazapine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of tucatinib is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with tucatinib due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Major) Avoid coadministration of tucatinib and mitotane due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and tucatinib. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with tucatinib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A4 inhibitors such as tucatinib could increase plasma concentrations of modafinil.
Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with tucatinib is necessary, due to increased mometasone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with tucatinib is necessary; decrease the dose of either drug as necessary. Morphine is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with tucatinib is necessary; decrease the dose of either drug as necessary. Morphine is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with tucatinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with tucatinib is contraindicated. Naloxegol is metabolized primarily by CYP3A4. Strong CYP3A4 inhibitors, such as tucatinib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with tucatinib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and tucatinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and tucatinib is a strong CYP3A and P-gp inhibitor.
Nelfinavir: (Moderate) Monitor for increased nelfinavir-related adverse effects if coadministered with tucatinib. Concurrent use may result in increased plasma concentrations of nelfinavir. Nelfinavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Neratinib: (Major) Avoid concomitant use of tucatinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with tucatinib is necessary. Netupitant is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with tucatinib is necessary. Nevirapine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
NIFEdipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with tucatinib as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and tucatinib. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If tucatinib is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and tucatinib is a strong inhibitor of CYP3A4.
Nimodipine: (Major) Avoid coadministration of nimodipine with tucatinib due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Nintedanib: (Moderate) Closely monitor for increased nintedanib side effects, including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension, if coadministration with tucatinib is necessary. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Concurrent use may increase the exposure and clinical effect of nintedanib. Nintedanib is a P-gp substrate, and a minor CYP3A4 substrate. Tucatinib is a P-gp inhibitor and a strong CYP3A4 inhibitor. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib exposure by 60%.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for increased toxicity of ritonavir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of ritonavir. Ritonavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and tucatinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with tucatinib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Norethindrone; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Norgestimate; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Olaparib: (Major) Avoid coadministration of olaparib with tucatinib due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after tucatinib is discontinued. Olaparib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A4 inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and tucatinib is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and tucatinib may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If tucatinib is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Olopatadine; Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with tucatinib is necessary, due to increased mometasone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and tucatinib. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with tucatinib is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half during coadministration of tucatinib; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ospemifene: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with tucatinib is necessary. Ospemifene is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with tucatinib is necessary. Oxybutynin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like tucatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If tucatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with tucatinib is necessary. Tucatinib is a strong CYP3A4 inhibitor and paclitaxel is metabolized by CYP3A4. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with tucatinib is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
Palbociclib: (Major) Avoid coadministration of palbociclib with tucatinib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If tucatinib is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of tucatinib) to the dose used before initiation of tucatinib. Palbociclib is primarily metabolized by CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Palovarotene: (Major) Avoid concomitant use of palovarotene and tucatinib due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with tucatinib. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and tucatinib, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Paricalcitol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor approximately doubled the exposure of paricalcitol.
Pazopanib: (Major) Avoid coadministration of pazopanib and tucatinib due to the potential for increased pazopanib exposure. Pazopanib is a CYP3A4 and P-gp substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and tucatinib due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If tucatinib is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of tucatinib. Pemigatinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and tucatinib due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If tucatinib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of tucatinib. Pexidartinib is a CYP3A substrate; tucatinib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%.
Phenobarbital: (Major) Avoid coadministration of tucatinib and phenobarbital due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of tucatinib and phenobarbital due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Phenytoin: (Major) Avoid coadministration of tucatinib and phenytoin due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Pimavanserin: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with tucatinib is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
Pimozide: (Contraindicated) Concurrent use of pimozide and tucatinib is contraindicated. Pimozide is metabolized primarily through CYP3A4, and tucatinib is a strong CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and tucatinib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. The exposure of tucatinib may also be increased. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of tucatinib use. Resume the previous dose of pirtobrutinib after tucatinib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and moderate CYP2C8 inhibitor and tucatinib is a CYP2C8 substrate and strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Ponatinib: (Major) Avoid coadministration of ponatinib and tucatinib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of tucatinib and consider alternative therapy. After tucatinib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting tucatinib. Ponatinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Pralsetinib: (Major) Avoid concomitant use of tucatinib and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and tucatinib is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%.
Prednisolone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of prednisolone with tucatinib is necessary, due to increased prednisolone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Prednisolone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Prednisone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of prednisone with tucatinib is necessary, due to increased prednisone exposure; Cushings syndrome and adrenal suppression could potentially occur with long-term use. Prednisolone, the active metabolite of prednisone, is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Primidone: (Major) Avoid coadministration of tucatinib and primidone due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and primidone is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and tucatinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and tucatinib is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Progesterone: (Moderate) Use caution if coadministration of tucatinib with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Tucatinib is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with tucatinib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and tucatinib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; tucatinib is a strong CYP3A4 inhibitor.
Quetiapine: (Major) Decrease the quetiapine dose to one sixth of the original dose if coadministered with tucatinib. Concurrent use may increase quetiapine exposure and adverse effects. When tucatinib is discontinued, increase the quetiapine dose by 6-fold. Quetiapine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased quetiapine exposure by approximately 6-fold.
Quinidine: (Moderate) Monitor for quinidine-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase quinidine exposure. Quinidine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Quinine: (Moderate) Monitor for quinine-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase quinine exposure. Quinine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Quizartinib: (Major) Avoid concomitant use of tucatinib with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Quizartinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with tucatinib is necessary. Ramelteon is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
Ranolazine: (Contraindicated) Coadministration of ranolazine with tucatinib is contraindicated as concurrent use may increase ranolazine exposure. Ranolazine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of another strong CYP3A4 inhibitor increased ranolazine exposure by 220%.
Regorafenib: (Major) Avoid coadministration of regorafenib with tucatinib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Relugolix: (Major) Avoid concomitant use of relugolix and oral tucatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer tucatinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral tucatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer tucatinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Repaglinide: (Major) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with tucatinib is necessary. Repaglinide is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with tucatinib due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a CYP3A and P-gp substrate and tucatinib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A and P-gp inhibitor increased repotrectinib exposure by 5.9-fold.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as tucatinib, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Ribociclib: (Major) Avoid coadministration of ribociclib with tucatinib due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If tucatinib is discontinued, resume the previous ribociclib dose after at least 5 half-lives of tucatinib. Ribociclib is a CYP3A4 substrate. Tucatinib is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with tucatinib due to the potential for significantly increased exposure to ribociclib. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If tucatinib is discontinued, resume the previous ribociclib dose after at least 5 half-lives of tucatinib. Ribociclib is a CYP3A4 substrate. Tucatinib is a strong CYP3A4 inhibitor. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers.
Rifabutin: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with tucatinib is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with CYP3A4 inhibitors may significantly increase the plasma concentration of rifabutin.
Rifampin: (Major) Avoid coadministration of tucatinib and rifampin due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and rifampin is a strong CYP3A4/moderate CYP2C8 inducer. Coadministration with rifampin decreased tucatinib exposure by 50%.
Rifapentine: (Major) Avoid coadministration of tucatinib and rifapentine due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and rifapentine is a strong CYP3A4 inducer and moderate CYP2C8 inducer. Coadministration with another strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with tucatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and tucatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Rimegepant: (Major) Avoid coadministration of rimegepant with tucatinib; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
Riociguat: (Major) Consider a starting dose of 0.5 mg PO 3 times daily when initiating riociguat in patients receiving tucatinib; concurrent use may increase riociguat exposure. Monitor for signs and symptoms of hypotension on initiation and during treatment with tucatinib. Consider a dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Riociguat is a substrate of CYP3A4 and P-glycoprotein (P-gp); tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with tucatinib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Ritonavir: (Moderate) Monitor for increased toxicity of ritonavir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of ritonavir. Ritonavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Rivaroxaban: (Major) Avoid coadministration of rivaroxaban and tucatinib; significant increases in rivaroxaban exposure may occur which may increase the bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Tucatinib is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with tucatinib is necessary; carefully weigh the risk against the benefit. Roflumilast is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased roflumilast exposure by 99%.
Romidepsin: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with tucatinib. Romidepsin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with tucatinib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of tucatinib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Salmeterol: (Major) Avoid concomitant use of salmeterol with tucatinib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Saquinavir: (Moderate) Monitor for increased toxicity of saquinavir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of saquinavir. Saquinavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with tucatinib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor for an increase in estrogenic-related adverse reactions (e.g., nausea, breast tenderness) if coadministration of ethinyl estradiol with tucatinib is necessary. Ethinyl estradiol is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased segesterone-related adverse effects if coadministered with tucatinib. Concurrent use may result in increased exposure of segesterone. Segesterone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and tucatinib due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. Tucatinib exposure may also be increased leading to increased risk of adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently and monitor for tucatinib-related adverse reactions. If tucatinib is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of tucatinib. Selpercatinib is a CYP3A4 substrate and moderate CYP2C8 inhibitor; tucatinib is a CYP2C8 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%.
Selumetinib: (Major) Avoid coadministration of selumetinib and tucatinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If tucatinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of tucatinib. Selumetinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Sildenafil: (Major) Coadministration with tucatinib is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving tucatinib. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Tucatinib is a strong CYP3A4 inhibitor and sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Contraindicated) Concurrent use of silodosin and tucatinib is contraindicated due to increased plasma concentrations of silodosin resulting in an increase of treatment-related adverse reactions. Silodosin is extensively metabolized by CYP3A4 and is a P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration with another strong CYP3A4 inhibitor increased silodosin exposure by 2.9-fold to 3.2-fold.
Simvastatin: (Contraindicated) Concurrent use of simvastatin and tucatinib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Siponimod: (Moderate) Concomitant use of siponimod and tucatinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and tucatinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and tucatinib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Solifenacin: (Major) If coadministered with tucatinib, do not exceed a 5 mg daily dose of solifenacin in adults; do not exceed the initial starting dose in pediatric patients. The plasma concentrations of solifenacin may be elevated when administered concurrently with tucatinib. Solifenacin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold.
Sonidegib: (Major) Avoid coadministration of sonidegib with tucatinib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
Sparsentan: (Major) Avoid concomitant use of sparsentan and tucatinib. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of tucatinib and St. John's Wort due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if tucatinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like tucatinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If tucatinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Major) Avoid coadministration of tucatinib with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and tucatinib is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentration if coadministration with tucatinib is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; tucatinib is a strong CYP3A4 inhibitor.
Tadalafil: (Major) Avoid coadministration of tadalafil and tucatinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of tucatinib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as tucatinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with tucatinib is necessary. Talazoparib is a P-gp substrate and tucatinib is a P-gp inhibitor.
Tamsulosin: (Major) Concurrent use of tamsulosin and tucatinib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4, and strong inhibitors of CYP3A4, such as tucatinib, are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with tucatinib as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Temsirolimus: (Major) Avoid coadministration of temsirolimus and tucatinib due to the risk of increased temsirolimus exposure resulting in an increased risk of adverse reactions. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. If tucatinib is discontinued, resume the original temsirolimus dose after a washout period of approximately 1 week. Temsirolimus is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration with another strong CYP3A4 inhibitor did not have a significant effect on temsirolimus exposure, but increased the exposure of sirolimus (the primary and active metabolite) by 3.1-fold.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with tucatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with tucatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Teriflunomide: (Moderate) Closely monitor for tucatinib-related adverse reactions if coadministration with teriflunomide is necessary due to the risk of increased tucatinib exposure. Tucatinib is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor.
Tezacaftor; Ivacaftor: (Major) If tucatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with tucatinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and tucatinib if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; tucatinib is a strong CYP3A4 inhibitor.
Ticagrelor: (Major) Avoid coadministration of ticagrelor with tucatinib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase the exposure of tinidazole. Tinidazole is a CYP3A4 substrate and tucatinib is a strong CYP3A inhibitor.
Tipranavir: (Moderate) Coadministration of tipranavir with tucatinib may result in increased tipranavir exposure, leading to an increase in tipranavir-related adverse effects. Tipranavir is a P-glycoprotein (P-gp) substrate and tucatinib is a P-gp inhibitor.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with tucatinib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with tucatinib. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with tucatinib. Concurrent use may increase tolterodine exposure. Tucatinib is a strong CYP3A inhibitor. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and tucatinib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Topotecan: (Major) Avoid coadministration of tucatinib with oral topotecan due to increased topotecan exposure; tucatinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and tucatinib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Avoid coadministration of tucatinib with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with tucatinib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with tucatinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of tucatinib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with tucatinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of tucatinib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with tucatinib. Coadministration may increase the exposure of verapamil. Tucatinib is a strong inhibitor of CYP3A4; verapamil is a substrate of CYP3A4.
Trazodone: (Major) Avoid coadministration of trazodone with tucatinib due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
Triamcinolone: (Moderate) Tucatinib may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Triazolam: (Contraindicated) Concomitant use of tucatinib with triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Triazolam is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Consider safer alternatives if a benzodiazepine must be administered in combination with tucatinib. Benzodiazepines not metabolized by the CYP3A4 enzyme (e.g., lorazepam, oxazepam) are less likely to be affected by strong CYP3A4 inhibitors.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and tucatinib is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant.
Ulipristal: (Minor) Concomitant use of ulipristal and tucatinib may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold.
Umeclidinium; Vilanterol: (Moderate) Caution is warranted when tucatinib is administered with vilanterol as there is a potential for elevated vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Vilanterol is a substrate of CYP3A4 and tucatinib is a strong CYP3A4 inhibitor.
Upadacitinib: (Major) During concomitant use of upadacitinib and tucatinib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with tucatinib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Vamorolone: (Major) Decrease the vamorolone dose to 4 mg/kg once daily (max: 200 mg) and monitor for adverse effects if concomitant use with tucatinib is necessary. Concomitant use may increase vamorolone exposure and the risk for vamorolone-related adverse effects. Vamorolone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased vamorolone overall exposure by 44%.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with tucatinib due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and tucatinib; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with tucatinib cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of tucatinib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of tucatinib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with tucatinib. Coadministration may increase the exposure of verapamil. Tucatinib is a strong inhibitor of CYP3A4; verapamil is a substrate of CYP3A4.
Vilazodone: (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with tucatinib is necessary; the original dose of vilazodone can be resumed if tucatinib is discontinued. Vilazodone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vilazodone exposure by 50%.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with tucatinib is necessary. Vinblastine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Avoid coadministration of vincristine with tucatinib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Vincristine: (Major) Avoid coadministration of vincristine with tucatinib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with tucatinib is necessary. Vinorelbine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and tucatinib is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vorapaxar: (Major) Avoid coadministration of vorapaxar with tucatinib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
Voriconazole: (Moderate) Monitor for increased voriconazole-related adverse effects if coadministered with tucatinib as concurrent use may increase voriconazole exposure. Voriconazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased voriconazole exposure by 79%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with tucatinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Tucatinib is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zaleplon: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with tucatinib is necessary. Concurrent use may increase zaleplon exposure. Zaleplon is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with tucatinib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of tucatinib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
Ziprasidone: (Moderate) Monitor for ziprasidone-related adverse effects, including QT prolongation, CNS effects, and extrapyramidal symptoms, if coadministered with tucatinib. Concurrent use may increase the exposure of ziprasidone. Ziprasidone is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of ziprasidone by approximately 35% to 40%.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with tucatinib is necessary. Concurrent use may increase zolpidem exposure. Zolpidem is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
Zuranolone: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with tucatinib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, it inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation; it also showed antitumor activity in HER2-expressing cells. In vivo, tucatinib inhibited the growth of HER2-expressing tumors. The combination of tucatinib and trastuzumab showed increased antitumor activity in vitro and in vivo compared to either drug alone.
Tucatinib is administered orally. It is 97.1% bound to plasma proteins at clinically relevant concentrations. The geometric mean apparent volume of distribution at steady-state is approximately 903 liters (CV, 42%) in patients with metastatic breast cancer and 829 liters (CV, 21%) in patients with metastatic colorectal cancer. Concentrations of tucatinib and its metabolite, ONT-993, in the cerebrospinal fluid were comparable to unbound plasma concentrations. In plasma, 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned. The effective half-life of tucatinib at steady-state is approximately 11.9 hours and the apparent clearance was 53 liters/hour (CV, 43%) in patients with metastatic breast cancer. The effective half-life of tucatinib at steady-state in patients with metastatic colorectal cancer is approximately 16.4 hours and the apparent clearance was 89 liters/hour (CV, 49%). The time to steady-state was approximately 4 days. After a single oral dose of radiolabeled tucatinib (300 mg), approximately 86% of the dose was recovered in feces (unchanged drug, 16%) and 4.1% in the urine. Ninety percent of the total radiolabeled dose was recovered within 13 days.
Affected cytochrome P450 isoenzymes: CYP2C8, CYP3A, P-glycoprotein (P-gp)
Tucatinib is primarily metabolized by CYP2C8 and to a lesser extent by CYP3A. Coadministration with rifampin (a strong CYP3A4/moderate CYP2C8 inducer) decreased the AUC of tucatinib by approximately half; avoid coadministration with strong CYP3A4 inducers or moderate CYP2C8 inducers. Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased the AUC of tucatinib by 1.3-fold; tucatinib may be administered with CYP3A4 inhibitors without dose adjustments or additional monitoring. Coadministration with gemfibrozil (a strong CYP2C8 inhibitor) increased the AUC of tucatinib by 3-fold; avoid coadministration with moderate and strong CYP2C8 inhibitors. Tucatinib is a strong time-dependent CYP3A inhibitor and a weak inhibitor of CYP2C8. It is a P-gp inhibitor and substrate, as well as a substrate of BCRP. It also inhibits MATE1/MATE2-K mediated transport of metformin and OCT2/MATE1-mediated transport of creatinine.
-Route-Specific Pharmacokinetics
Oral Route
The median time to peak plasma concentration of tucatinib (Tmax) was approximately 2 hours (range, 1 to 4 hours). The AUC and Cmax of tucatinib increase proportionally over a dose range of 50 mg to 300 mg (0.17 to 1 times the approved recommended dose). At steady-state, the Cmax, Cmin, and AUC of tucatinib in patients with metastatic breast cancer were 747 ng/mL (CV, 45%), 288 ng/mL (CV, 59%), and 5,620 ng*hour/mL (CV, 43%). The Cmax, Cmin, and AUC of tucatinib at steady-state in patients with metastatic colorectal cancer were 405 ng/mL (CV, 45%), 197 ng/mL (CV, 63%), and 3,370 ng*hour/mL (CV, 49%). The geometric mean AUC accumulation ratios ranged from 2-fold to 2.5-fold (CV, 26% to 28%).
The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful. After a single dose of tucatinib, the mean AUC increased by 1.5-fold after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein). The Tmax shifted from 1.5 to 4 hours, and the Cmax was unchanged.
-Special Populations
Hepatic Impairment
Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment did not have a clinically relevant effect on tucatinib exposure. The AUC of tucatinib increased by 1.6-fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.
Renal Impairment
Mild to moderate renal impairment (CrCl 30 to 89 mL/min) did not have a clinically significant effect on the pharmacokinetics of tucatinib. The effect of severe renal impairment (CrCl less than 30 mL/min) on the pharmacokinetics of tucatinib is unknown.
Geriatric
Age (18 to 77 years) did not have a clinically meaningful effect on tucatinib exposure.
Gender Differences
Sex did not have a clinically meaningful impact on tucatinib exposure.
Ethnic Differences
Ethnicity (White, Black, Asian) did not have a clinically meaningful effect on tucatinib exposure.
Obesity
Weight (41 to 146 kg) did not have a clinically meaningful effect on tucatinib exposure.
Other
Albumin levels (19 to 52 g/liters) did not have a clinically meaningful effect on tucatinib exposure.