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  • CLASSES

    Small Molecule Antineoplastic EGFR (HER1) Inhibitors
    Small Molecule Antineoplastic HER2/neu Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Epidermal growth factor receptor (EGFR) kinase inhibitor
    Used for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 (L858R) substitution mutations
    Monitor for diarrhea, dermatologic reactions, and symptoms of pneumonitis; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary

    COMMON BRAND NAMES

    Vizimpro

    HOW SUPPLIED

    Dacomitinib/VIZIMPRO Oral Tab: 15mg, 30mg, 45mg

    DOSAGE & INDICATIONS

    For the first-line treatment of metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
    NOTE: Select patients based on the presence of an exon 19 deletion or exon 21 (L858R) substitution mutation in tumor specimens. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    45 mg PO once daily 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, randomized, open-label clinical trial, patients with previously untreated, unresectable, metastatic NSCLC with EGFR exon 19 deletion or exon 21 (L858R) substitution, or recurrent disease after a minimum of 12 months after systemic therapy, were treated with dacomitinib (n = 227) or gefitinib (n = 225). Treatment with dacomitinib significantly improved progression-free survival (PFS) (14.7 months vs. 9.2 months). The overall response rate was similar between arms (75% vs. 72%), with a median duration of 14.8 months versus 8.3 months, respectively.[63584]

    MAXIMUM DOSAGE

    Adults

    45 mg PO once daily.

    Geriatric

    45 mg PO once daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild or moderate hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN) with AST greater than ULN; OR total bilirubin 1.1 to 3 times ULN and any AST): No dose adjustment is recommended.
    Severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST): The recommended dose of dacomitinib has not been established.

    Renal Impairment

    Mild to moderate renal impairment (CrCL 30 to 89 mL/min): No dosage adjustment is recommended.
    Severe renal impairment (CrCL less than 30 mL/min): The recommended dose of dacomitinib has not been established.[63584]

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Dacomitinib may be administered with or without food.
    Take dacomitinib at the same time each day.
    If the patient vomits or misses a dose, do not administer an additional dose or make up a missed dose. Continue with the next scheduled dose.[63584]

    STORAGE

    Vizimpro:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Chronic lung disease (CLD), interstitial lung disease, pneumonitis, pulmonary disease

    Use dacomitinib with caution in patients with a history of pulmonary disease or chronic lung disease (CLD). Severe and fatal interstitial lung disease/pneumonitis has occurred with the use of dacomitinib in clinical trials (n = 394); patients with a history of interstitial lung disease or interstitial pneumonitis were excluded from the largest clinical trial (n = 227). Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Hold dacomitinib and promptly investigate for ILD in patients who present with worsening of respiratory symptoms, including dyspnea, cough, and fever. If interstitial lung disease is diagnosed, dacomitinib should be discontinued and appropriate treatment instituted as necessary.[63584]

    Diarrhea

    Severe and fatal diarrhea occurred in patients treated with dacomitinib in clinical trials. Promptly initiate anti-diarrheal treatment (e.g., loperamide or diphenoxylate hydrochloride with atropine sulfate) for diarrhea. If grade 2 or higher diarrhea occurs, an interruption of therapy or dose adjustment may be necessary.[63584]

    Serious rash, sunlight (UV) exposure

    Serious rash and exfoliative skin reactions occurred in patients treated with dacomitinib in clinical trials. The incidence and severity of may increase with sunlight (UV) exposure. Initiate the use of moisturizers and appropriate measures to limit sun exposure at the time of initiation of dacomitinib therapy. Treat a grade 1 rash with topical antibiotics and topical steroids. An interruption of therapy and dose reduction may be necessary for grade 2 or higher rash.[63584]

    Geriatric

    Monitor closely for adverse reactions when dacomitinib is administered to geriatric patients. Exploratory analyses of patients age 65 or older (n = 158) in 5 clinical studies with EGFR mutation-positive NSCLC who received dacomitinib (n = 394) suggest a higher incidence of grade 3 and 4 adverse reactions (67% vs. 56%), more frequent dose interruptions (53% vs. 45%), and more frequent discontinuations for adverse reactions (24% vs. 10%) compared to younger patients.[63584]

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during dacomitinib treatment and for at least 17 days after the last dose. Although there are no adequately controlled studies in pregnant humans, dacomitinib 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 dacomitinib should be apprised of the potential hazard to the fetus. In animal reproduction studies, administration of dacomitinib to pregnant rats during organogenesis increased the incidence of postimplantation loss and reduced fetal body weight at approximately 1.2 times the exposure based on AUC of the 45-mg human dose. Disruption or depletion of EGFR in mouse models has shown EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling in mice can prevent implantation and can cause embryo-fetal loss during various stages of gestation (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/neonates.[63584]

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during dacomitinib treatment. Dacomitinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 17 days after treatment with dacomitinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of dacomitinib. Women who become pregnant while receiving dacomitinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of dacomitinib on human fertility, reversible male and female infertility has been observed in animal studies.[63584]

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from dacomitinib, advise women to discontinue breast-feeding during treatment and for 17 days after the final dose. It is not known whether dacomitinib is present in human milk, although many drugs are excreted in human milk.[63584]

    ADVERSE REACTIONS

    Severe

    rash / Early / 21.0-23.0
    diarrhea / Early / 8.0-11.3
    hypokalemia / Delayed / 7.0-7.0
    lymphopenia / Delayed / 6.0-6.0
    stomatitis / Delayed / 4.4-4.4
    anorexia / Delayed / 3.1-3.1
    hyponatremia / Delayed / 2.9-2.9
    dyspnea / Early / 2.2-2.2
    weight loss / Delayed / 2.2-2.2
    asthenia / Delayed / 2.2-2.2
    pneumonitis / Delayed / 0.5-1.8
    xerosis / Delayed / 1.8-1.8
    exfoliative dermatitis / Delayed / 1.8-1.8
    keratitis / Delayed / 1.8-1.8
    elevated hepatic enzymes / Delayed / 0.5-1.4
    hypocalcemia / Delayed / 1.4-1.4
    nausea / Early / 1.3-1.3
    infection / Delayed / 1.3-1.3
    hyperglycemia / Delayed / 1.0-1.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0.9-0.9
    pruritus / Rapid / 0.9-0.9
    musculoskeletal pain / Early / 0.9-0.9
    anemia / Delayed / 0.9-0.9
    hyperbilirubinemia / Delayed / 0.5-0.5
    hypomagnesemia / Delayed / 0.5-0.5
    alopecia / Delayed / 0.4-0.4
    insomnia / Early / 0.4-0.4

    Moderate

    hypoalbuminemia / Delayed / 44.0-44.0
    conjunctivitis / Delayed / 19.0-19.0
    constipation / Delayed / 13.0-13.0
    oral ulceration / Delayed / 12.0-12.0
    chest pain (unspecified) / Early / 10.0-10.0
    dehydration / Delayed / 1.3-1.3

    Mild

    cough / Delayed / 21.0-21.0
    vomiting / Early / 9.0-9.0
    fatigue / Early / 9.0-9.0
    dysgeusia / Early / 7.0-7.0
    hypertrichosis / Delayed / 1.3-1.3
    onycholysis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with dacomitinib may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dacomitinib is a strong inhibitor of CYP2D6.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Acetaminophen; Dextromethorphan: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Amitriptyline: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Amoxapine: (Moderate) Monitor for increased toxicity of amoxapine, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase serum concentrations of amoxapine. Amoxapine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of omeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Amphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Amphetamine; Dextroamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Amphetamines: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Aripiprazole: (Major) Dacomitinib, a strong inhibitor of CYP2D6, may decrease the metabolism of CYP2D6 substrates such as aripiprazole. Decreased metabolism of aripiprazole may lead to adverse effects such as extrapyramidal symptoms, QT prolongation, and torsade de pointes (TdP). The manufacturer of aripiprazole recommends that the oral aripiprazole dose be reduced to one-half of the usual dose when coadministered with strong CYP2D6 inhibitors. Adults receiving 300 mg or 400 mg of Abilify Maintena should have a dose reduction to 200 mg or 300 mg, respectively, during coadministration of a strong CYP2D6 inhibitor if used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP2D6 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with dacomitinib may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dacomitinib is a strong inhibitor of CYP2D6.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Aspirin, ASA; Omeprazole: (Major) Avoid coadministration of omeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Atomoxetine: (Major) A lower initial dose of atomoxetine is recommended in patients receiving dacomitinib due to the potential for increased atomoxetine exposure and related adverse effects. In children and adolescents up to 70 kg receiving dacomitinib, atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving dacomitinib, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation). Dacomitinib is a strong CYP2D6 inhibitor; atomoxetine is a CYP2D6 substrate. Coadministration of a strong CYP2D6 inhibitor and atomoxetine in extensive metabolizers of CYP2D6, increased atomoxetine steady-state plasma concentrations by approximately 6 to 8-fold. This increase is similar to exposures observed in poor metabolizers. Concurrent use of a strong CYP2D6 inhibitor with atomoxetine in poor metabolizers is not expected to increase atomoxetine exposure.
    Benzphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Brexpiprazole: (Major) Reduce the dose of brexpiprazole if coadministered with dacomitinib in patients with schizophrenia. No dosage adjustment is needed during concurrent use in patients who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations. In schizophrenia patients, reduce the brexpiprazole dose to half the usual dose if coadministered with dacomitinib; reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and dacomitinib are coadministered with a strong/moderate CYP3A4 inhibitor. Dacomitinib is a strong CYP2D6 inhibitor. Brexpiprazole is a CYP2D6 and CYP3A4 substrate. Concomitant use of strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Administer dacomitinib at least 6 hours before or 10 hours after taking famotidine due to the risk of decreased plasma concentrations of dacomitinib which may impact efficacy. Although the effect of H2-blockers on dacomitinib pharmacokinetics has not been studied, coadministration with a proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Carvedilol: (Moderate) Monitor for increased toxicity of carvedilol if coadministered with dacomitinib. Coadministration may increase serum concentrations of carvedilol. Carvedilol is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Cevimeline: (Moderate) Monitor for increased toxicity of cevimeline if coadministered with dacomitinib. Coadministration may increase serum concentrations of cevimeline. Cevimeline is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Dextromethorphan: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with dacomitinib may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dacomitinib is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with dacomitinib may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dacomitinib is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    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.
    Cimetidine: (Moderate) Administer dacomitinib at least 6 hours before or 10 hours after taking cimetidine due to the risk of decreased plasma concentrations of dacomitinib which may impact efficacy. Although the effect of H2-blockers on dacomitinib pharmacokinetics has not been studied, coadministration with a proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Clomipramine: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with dacomitinib and monitor for adverse reactions. If dacomitinib 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 a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Codeine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with dacomitinib may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. 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 increase of codeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Dacomitinib is a strong inhibitor of CYP2D6.
    Desipramine: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Deutetrabenazine: (Major) Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if used concurrently with dacomitinib. Dacomitinib is a strong CYP2D6 inhibitor, and the metabolites of deutetrabenazine, alpha- and beta-HTBZ, are CYP2D6 substrates. The systemic exposure of alpha- and beta-HTBZ may be increased resulting in an increase in deutetrabenazine-related adverse reactions, like QT prolongation and drowsiness.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Dextroamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dextromethorphan; Quinidine: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with dacomitinib may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of dacomitinib could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If dacomitinib is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Dacomitinib is a strong inhibitor of CYP2D6.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Donepezil: (Moderate) Monitor for increased toxicity of donepezil, such as GI or cholinergic adverse effects, if coadministered with dacomitinib. Coadministration may increase serum concentrations of donepezil. Donepezil is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Donepezil; Memantine: (Moderate) Monitor for increased toxicity of donepezil, such as GI or cholinergic adverse effects, if coadministered with dacomitinib. Coadministration may increase serum concentrations of donepezil. Donepezil is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Doxepin: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Doxorubicin: (Major) Avoid coadministration of dacomitinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a substrate of CYP2D6; dacomitinib is a strong CYP2D6 inhibitor. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effects of doxorubicin.
    Duloxetine: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with dacomitinib. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Dacomitinib is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
    Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of dacomitinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and dacomitinib is a strong CYP2D6 inhibitor. Concomitant treatment with another strong CYP2D6 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively.
    Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of dacomitinib and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily; however, coadministration of eliglustat with both dacomitinib and a strong or moderate CYP3A inhibitor is contraindicated. Dacomitinib is a strong inhibitor of CYP2D6; eliglustat is a CYP2D6 and CYP3A substrate. Coadministration of eliglustat with CYP2D6 inhibitors, such as dacomitinib, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Esomeprazole: (Major) Avoid coadministration of esomeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Famotidine: (Moderate) Administer dacomitinib at least 6 hours before or 10 hours after taking famotidine due to the risk of decreased plasma concentrations of dacomitinib which may impact efficacy. Although the effect of H2-blockers on dacomitinib pharmacokinetics has not been studied, coadministration with a proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Famotidine; Ibuprofen: (Moderate) Administer dacomitinib at least 6 hours before or 10 hours after taking famotidine due to the risk of decreased plasma concentrations of dacomitinib which may impact efficacy. Although the effect of H2-blockers on dacomitinib pharmacokinetics has not been studied, coadministration with a proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Flecainide: (Moderate) Monitor for increased toxicity of flecainide if coadministered with dacomitinib. Coadministration may increase serum concentrations of flecainide. Flecainide is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with dacomitinib is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and dacomitinib is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Haloperidol: (Moderate) Monitor for increased toxicity of haloperidol, such as extrapyramidal symptoms or QT prolongation, if coadministered with dacomitinib. Coadministration may increase serum concentrations of haloperidol. Haloperidol is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with dacomitinib. If dacomitinib is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP2D6 substrate. Dacomitinib is a strong inhibitor of CYP2D6. Coadministration of other strong CYP2D6 inhibitors increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by up to 3-fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half.
    Imipramine: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Lansoprazole: (Major) Avoid coadministration of lansoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of lansoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Lansoprazole; Naproxen: (Major) Avoid coadministration of lansoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Lisdexamfetamine: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and dacomitinib. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    Maprotiline: (Moderate) Monitor for increased toxicity of maprotiline, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase serum concentrations of maprotiline. Maprotiline is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Methadone: (Moderate) Concomitant use of methadone with dacomitinib may increase methadone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of methadone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to methadone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Methadone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Methamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Metoclopramide: (Major) Dose adjustments of oral metoclopramide are recommended when administered in combination with dacomitinib due to the risk of increased metoclopramide plasma concentrations and extrapyramidal adverse reactions. In patients with diabetic gastroparesis, avoid coadministration with dacomitinib. If coadministration cannot be avoided, the recommended dose of metoclopramide is 5 mg PO four times daily. In patients with gastroesophageal reflux, the recommended dose of metoclopramide is 5 mg PO four times daily or 10 mg PO three times daily when coadministered with dacomitinib. Metoclopramide is a substrate of CYP2D6 and dacomitinib is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor increased the metoclopramide Cmax and AUC by 40% and 90%, respectively.
    Metoprolol: (Moderate) Monitor for bradycardia, reduced blood pressure, and increased side effects of metoprolol if coadministered with dacomitinib. Coadministration may result in significantly increased metoprolol serum concentrations. An increase in metoprolol serum concentrations would decrease the cardioselectivity of metoprolol. Metoprolol is a primary substrate of CYP2D6; dacomitinib is a strong CYP2D6 inhibitor. In drug interaction studies, coadministration of metoprolol with another strong CYP2D6 inhibitor in CYP2D6 extensive metabolizers tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for bradycardia, reduced blood pressure, and increased side effects of metoprolol if coadministered with dacomitinib. Coadministration may result in significantly increased metoprolol serum concentrations. An increase in metoprolol serum concentrations would decrease the cardioselectivity of metoprolol. Metoprolol is a primary substrate of CYP2D6; dacomitinib is a strong CYP2D6 inhibitor. In drug interaction studies, coadministration of metoprolol with another strong CYP2D6 inhibitor in CYP2D6 extensive metabolizers tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life.
    Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with dacomitinib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Naproxen; Esomeprazole: (Major) Avoid coadministration of esomeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Nebivolol: (Major) Avoid the concomitant use of nebivolol and dacomitinib. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect. Nebivolol is metabolized by CYP2D6; dacomitinib is a strong CYP2D6 inhibitor. An 8-fold increase in the AUC and a 3-fold increase in Cmax for d-nebivolol was seen when nebivolol was coadministered with another strong CYP2D6 inhibitor.
    Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and dacomitinib. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect. Nebivolol is metabolized by CYP2D6; dacomitinib is a strong CYP2D6 inhibitor. An 8-fold increase in the AUC and a 3-fold increase in Cmax for d-nebivolol was seen when nebivolol was coadministered with another strong CYP2D6 inhibitor.
    Nizatidine: (Moderate) Administer dacomitinib at least 6 hours before or 10 hours after taking nizatidine due to the risk of decreased plasma concentrations of dacomitinib which may impact efficacy. Although the effect of H2-blockers on dacomitinib pharmacokinetics has not been studied, coadministration with a proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Nortriptyline: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    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 dacomitinib is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and dacomitinib may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If dacomitinib is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and dacomitinib is a strong CYP2D6 inhibitor.
    Omeprazole: (Major) Avoid coadministration of omeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of omeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid coadministration of omeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Pantoprazole: (Major) Avoid coadministration of pantoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Paroxetine: (Moderate) Monitor for increased toxicity of paroxetine if coadministered with dacomitinib. Coadministration may increase serum concentrations of paroxetine. Paroxetine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Perphenazine: (Moderate) Monitor for increased toxicity of perphenazine if coadministered with dacomitinib. Coadministration may increase serum concentrations of perphenazine. Perphenazine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Perphenazine; Amitriptyline: (Moderate) Monitor for increased toxicity of perphenazine if coadministered with dacomitinib. Coadministration may increase serum concentrations of perphenazine. Perphenazine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Pimozide: (Contraindicated) Coadministration of dacomitinib and pimozide is contraindicated, as concurrent use may result in increased exposure to pimozide. Elevated pimozide concentrations would be expected to augment the prolongation of the QTc interval associated with pimozide and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes. Pimozide is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Pitolisant: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking dacomitinib; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If dacomitinib is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold.
    Promethazine; Dextromethorphan: (Moderate) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    Propafenone: (Moderate) Monitor for increased toxicity of propafenone if coadministered with dacomitinib. Coadministration may increase serum concentrations of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
    Propranolol: (Moderate) Monitor for increased toxicity of propranolol if coadministered with dacomitinib. Coadministration may increase serum concentrations of propranolol. Propranolol is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased toxicity of propranolol if coadministered with dacomitinib. Coadministration may increase serum concentrations of propranolol. Propranolol is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Protriptyline: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Rabeprazole: (Major) Avoid coadministration of rabeprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with rabeprazole decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Ranitidine: (Major) Administer dacomitinib at least 6 hours before or 10 hours after taking ranitidine due to the risk of decreased plasma concentrations of dacomitinib which may impact efficacy. Although the effect of H2-blockers on dacomitinib pharmacokinetics has not been studied, coadministration with a proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Risperidone: (Major) Initiate risperidone at a reduced dose in patients receiving dacomitinib as increased plasma concentrations of risperidone and toxicity may occur. Do not exceed 8 mg PO per day of risperidone if these drugs are coadministered. For the long-acting risperidone injection, the current adult dosage should be closely monitored when dacomitinib is initiated or discontinued. An adjustment of the dose may be required. Risperidone is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 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.
    Tamoxifen: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with dacomitinib is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Dacomitinib is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Tamsulosin: (Moderate) Use caution if coadministration of dacomitinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and dacomitinib is a strong CYP2D6 inhibitor. Concomitant treatment with another strong CYP2D6 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively.
    Tetrabenazine: (Major) Do not exceed a maximum single dose of tetrabenazine of 25 mg and a daily dose of 50 mg when coadministered with dacomitinib. Additionally, monitor for adverse effects associated with tetrabenazine such as QT prolongation, excess sedation, and extrapyramidal symptoms. Coadministration may increase serum concentrations of tetrabenazine. The primary metabolites of tetrabenazine, alpha-dihydrotetrabenzaine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), are substrates for CYP2D6. Dacomitinib is a strong CYP2D6 inhibitor. In drug interaction studies, coadministration of tetrabenazine with another strong CYP2D6 inhibitor resulted in an increase in Cmax of approximately 30% and a 3-fold increase in AUC for alpha-HTBZ. The Cmax and AUC for beta-HTBZ increased 2.4-fold and 9-fold, respectively. The elimination half-life of alpha-HTBZ and beta-HTBZ were increased to approximately 14 hours.
    Thioridazine: (Contraindicated) Coadministration of dacomitinib and thioridazine is contraindicated, as concurrent use may result in increased exposure to thioridazine. Elevated thioridazine concentrations would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes. Thioridazine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Tramadol: (Moderate) Coadministration of dacomitinib with tramadol may decrease tramadol metabolism resulting in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. Tramadol is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Tramadol; Acetaminophen: (Moderate) Coadministration of dacomitinib with tramadol may decrease tramadol metabolism resulting in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. Tramadol is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Tricyclic antidepressants: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Trimipramine: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Valbenazine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as dacomitinib. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
    Venlafaxine: (Moderate) Monitor for increased toxicity of venlafaxine if coadministered with dacomitinib. Coadministration may increase serum concentrations of venlafaxine. Venlafaxine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Vortioxetine: (Major) Reduce the vortioxetine dose by one-half during coadministration with dacomitinib. Increase the dose back to the original level when dacomitinib is discontinued. Coadministration may increase vortioxetine serum concentrations. Vortioxetine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during dacomitinib treatment and for at least 17 days after the last dose. Although there are no adequately controlled studies in pregnant humans, dacomitinib 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 dacomitinib should be apprised of the potential hazard to the fetus. In animal reproduction studies, administration of dacomitinib to pregnant rats during organogenesis increased the incidence of postimplantation loss and reduced fetal body weight at approximately 1.2 times the exposure based on AUC of the 45-mg human dose. Disruption or depletion of EGFR in mouse models has shown EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling in mice can prevent implantation and can cause embryo-fetal loss during various stages of gestation (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/neonates.[63584]

    Due to the potential for serious adverse reactions in nursing infants from dacomitinib, advise women to discontinue breast-feeding during treatment and for 17 days after the final dose. It is not known whether dacomitinib is present in human milk, although many drugs are excreted in human milk.[63584]

    MECHANISM OF ACTION

    Dacomitinib irreversibly inhibits the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain activating mutations (exon 19 deletion or exon 21 (L858R) substitution mutations). Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications. In vitro, it also inhibitor the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations.[63584]

    PHARMACOKINETICS

    Dacomitinib is administered orally. In vitro binding to human plasma proteins is approximately 98% and is independent of drug concentrations from 250 ng/mL to 1,000 ng/mL. The geometric mean volume of distribution (Vd) of dacomitinib at steady state was 1,889 L (coefficient of variation (CV), 18%). Following a single oral dose in patients with cancer, the mean plasma half-life was 70 hours (CV, 21%) and the geometric mean apparent plasma clearance was 24.9 L/h (CV, 36%). Hepatic metabolism is the main route of clearance of dacomitinib, with oxidation and glutathione conjugation as the major pathways. Following oral administration of a single radiolabelled dose, O-desmethyl dacomitinib was the most abundant circulating metabolite, which had similar in vitro pharmacologic activity as dacomitinib. Seventy-nine percent (79%) of the radioactivity was recovered in feces (20% as unchanged drug) and 3% in urine (less than 1% as unchanged drug).[63584]
     
    Affected cytochrome P450 isoenzymes: CYP2D6, CYP3A4
    In vitro studies indicate that CYP2D6 was the major isoenzyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites. However, coadministration with multiple doses of a strong CYP2D6 inhibitor in healthy subjects increased the total AUC of dacomitinib plus O-desmethyl dacomitinib in plasma by approximately 6%, which is not considered clinically relevant. Dacomitinib is a strong CYP2D6 inhibitor, increasing the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 9.7-fold and 9.6-fold, respectively. In vitro, dacomitinib inhibits UGT 1A1, P-glycoprotein (P-gp), BCRP, and OCT1; is a substrate for P-gp and BCRP.[63584]

    Oral Route

    The mean absolute bioavailability of dacomitinib is 80% after oral administration. The maximum concentration (Cmax) and AUC at steady-state increased proportionally over the dose range of 2 mg to 60 mg by mouth once daily (0.04 to 1.3 times the recommended dose) in patients with cancer. In a dose-finding clinical study in patients with solid tumors, the geometric mean Cmax of dacomitinib at steady-state was 108 ng/mL (CV, 35%) and the AUC was 2,213 ng x h/mL (CV, 35%) at the recommended dose of 45 mg once daily. The median time to reach maximum concentration (Tmax) occurred at approximately 6 hours (range, 2 to 24 hours) after a single 45 mg dose in patients with cancer. Steady-state was achieved within 14 days following repeated dosing; the estimated geometric mean accumulation ratio was 5.7 (CV, 28%) based on AUC. The steady-state plasma trough concentration of the active metabolite, O-desmethyl dacomitinib, ranged from 7.9% to 19% of the parent. Administration with a high-fat, high-calorie meal had no clinically meaningful effect on dacomitinib pharmacokinetics.[63584]
     
    Gastric pH has an impact on dacomitinib exposure. Coadministration with a proton-pump inhibitor decreased the dacomitinib Cmax by 51% and AUC by 39%; however, coadministration with a local antacid did not cause clinically relevant changes in dacomitinib exposure. The effect of H2 receptor antagonists on dacomitinib pharmacokinetics has not been studied.